U.S. patent number 11,098,052 [Application Number 16/081,683] was granted by the patent office on 2021-08-24 for 4-azapodophylotoxins compounds.
This patent grant is currently assigned to Arizona Board of Regents on behalf of Arizona State University. The grantee listed for this patent is George Robert Pettit. Invention is credited to George Robert Pettit, Justin Searcy.
United States Patent |
11,098,052 |
Pettit , et al. |
August 24, 2021 |
4-azapodophylotoxins compounds
Abstract
The present disclosure relates to 4-azapodophylotoxins
compounds, pharmaceutical compositions comprising such compounds,
kits, and methods for using such compounds or pharmaceutical
compositions.
Inventors: |
Pettit; George Robert (Paradise
Valley, AZ), Searcy; Justin (Loveland, CO) |
Applicant: |
Name |
City |
State |
Country |
Type |
Pettit; George Robert |
Paradise Valley |
AZ |
US |
|
|
Assignee: |
Arizona Board of Regents on behalf
of Arizona State University (Scottsdale, AZ)
|
Family
ID: |
1000005762351 |
Appl.
No.: |
16/081,683 |
Filed: |
March 2, 2017 |
PCT
Filed: |
March 02, 2017 |
PCT No.: |
PCT/US2017/020488 |
371(c)(1),(2),(4) Date: |
August 31, 2018 |
PCT
Pub. No.: |
WO2017/151947 |
PCT
Pub. Date: |
September 08, 2017 |
Prior Publication Data
|
|
|
|
Document
Identifier |
Publication Date |
|
US 20190077808 A1 |
Mar 14, 2019 |
|
Related U.S. Patent Documents
|
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
|
62302236 |
Mar 2, 2016 |
|
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P
35/00 (20180101); C07D 491/048 (20130101); C07D
491/153 (20130101); C07D 491/14 (20130101) |
Current International
Class: |
C07D
491/048 (20060101); C07D 491/14 (20060101); A61P
35/00 (20060101); C07D 491/153 (20060101) |
Field of
Search: |
;546/65 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
|
|
|
|
|
|
|
1103554 |
|
May 2001 |
|
EP |
|
WO 1997/09984 |
|
Mar 1997 |
|
WO |
|
WO-2005097802 |
|
Oct 2005 |
|
WO |
|
Other References
Atsuo Babs et al Studies on disease-modifying antirheumatic Drugs.
. . (Year: 1999). cited by examiner .
Yukio Hitotsuyanagi et al , A facile Synthesis of the 4-Aza-analogs
of 1-arylnaphthalene Lignans Chinensis, Justicidin B, and Taiwanin
C (Year: 1997). cited by examiner .
Yukio Hitotsuyanagi et al
4-Aza-2,3-dehydro-4-deoxypodophyllotoxins: Simple
Aza-podophyllotoxin Analogues Possessing Potent Cytotoxicity.
(Year: 2000). cited by examiner .
Ajay Kumar et al (Year: 2010). cited by examiner .
Mirko Andreoli et al , Identification of the first Inhibitor of the
GBP1:PIM1 interaction. (Year: 2014). cited by examiner .
English abstract, Caplus of EP 1103554 (Year: 2001). cited by
examiner .
George Pettit et al. Journal of Natural Products , Antineoplastic
Agents, 585. Isolation of Bridelia ferruginea Anticancer
Podophyllotoxins and Synthesis of 4-Aza-podophyllotoxin Structural
Modifications, (Year: 2016). cited by examiner .
Zhang, Z. W.; Zhang, J. Q.; Hui, J.-Q.; Chen, L. H.; Chen, S.-W.;
Tian, X. Eur. J. Med. Chem. 2010, 45, 1673-1677. cited by applicant
.
Addae-Mensah, I.; Achenbach, H. Phytochemistry 1985, 24, 1817-1819.
cited by applicant .
Addae-Mensah, I.; Munenge, R. W. Fitoterapia 1989, 60, 359-362.
cited by applicant .
Beletskaya, I. P.; Cheprakov, A. V. Coord. Chem. Rev. 2004, 248,
2337-2364. cited by applicant .
Botes, M. G.; Pelly, S. C.; Blackie, M. A. L.; Kornienko, A.; van
Otterlo, W. A. L. Chem. Heterocycl. Compd. 2014,50, 119-137. cited
by applicant .
Broomhead, A. J.; Dewick, P. M. Phytochemistry 1990, 29, 3831-3837.
cited by applicant .
Castro, A. M.; del Corral, J. M. M.; Garcia, P.A.; Rojo, M. V.; de
la Iglesia-Vicente, J.; Mollinedo, F.; Cuevas, C.; San Feliciano,
A. J. Med. Chem. 2010, 53, 983-993. cited by applicant .
Chang, L. C.; Song, L. L.; Park, E. J.; Luyengi, L.; Lee, K. J.;
Farnsworth, N. R.; Pezzuto, J. M.; Kinghorn, A. D. J. Nat. Prod.
2000, 63, 1235-1238. cited by applicant .
Che, Z.; Yu, X.; Zhi, X.; Fan, L.; Yao, X.; Xu, H. J. Agric. Food.
Chem. 2013, 61,8148-8155. cited by applicant .
Cimanga, K.; Ying, L.; De Bruyne, T.; Apers, S.; Cos, P.; Hermans,
N.; Bakana, P.; Tona, L.; Kambu, K.; Kalenda, D. T.; Pieters, L.;
Vanden Berghe, D.; Vlietinck, A. J. J. Pharm. Pharmacol. 2001,53,
757-761. cited by applicant .
Dong, W.; Zhang, L.; Niu, Y.; Fan, D.; Wu, X.; Tang, X.; Cai, C.
Expert Opin. Drug. Deliv. 2013, 10, 559-571. cited by applicant
.
Dossena, A.; Marchelli, R.; Pochini, A. J. Chem. Soc., Chem.
Commun. 1974, 771-772. cited by applicant .
Eyberger, A. L.; Dondapati, R.; Porter, J. R. J. Nat. Prod. 2006,
69, 1121-1124. cited by applicant .
Giorgi-Renault, S. Ann. Pharm. Fr. 2005, 63, 63-68. cited by
applicant .
Hanauske, A. R.; Wuester, K. C.; Lehmer, A.; Rotter, M.; Schneider,
P.; Kaeser-Froelich, A.; Rastetter, J.; Depenbrock, H. Eur. J.
Cancer, Part A 1995, 31 A, 1677-1681. cited by applicant .
Hartwell, J. L.; Schrecker, A. W. In Fortschritte der Chemie
organischer Naturstoffe, vol. XV; Zechmeister, L., Ed.;
Springer-Verlag: Vienna, 1958, 83. cited by applicant .
Hearon, W. M.; MacGregor, W. S. Chem. Rev. 1955, 55, 957-1068.
cited by applicant .
Hitotsuyanagi, Y.; Fukuyo, M.; Tsuda, K.; Kobayashi, M.; Ozeki, A.;
Itokawa, H.; Takeya, K. Bioorg. Med. Chem. Lett. 2000, 10, 315-317.
cited by applicant .
Ikeda, R.; Nagao, T.; Okabe, H.; Nakano, Y.; Matsunaga, H.; Katano,
M.; Mori, M. Chem. Pharm. Bull. 1998, 46,871-874. cited by
applicant .
International Search Report and Written Opinion dated Jul. 14, 2017
in International Patent Application No. PCT/US2017/020488. cited by
applicant .
Iwu, M. M.; Court, W. E. Planta Med. 1980, 38, 260-263. cited by
applicant .
Jin, Y.; Liu, J.; Huang, W.-T.; Chen, S. W.; Hui, L. Eur. J. Med.
Chem. 2011, 46, 4056-4061. cited by applicant .
Kamal, A.; Mallareddy, A.; Suresh, P.; Nayak, L.; Shetti, R. V. C.
R. N. C.; Rao, N. S.; Tamboli, J. R.; Shaik, T. B.; Vishnuvardhan,
M. V. P. S.; Ramakrishna, S. Eur. J. Med. Chem. 2012, 47, 530-545.
cited by applicant .
Kamal, A.; Suresh, P.; Ramaiah, M. J.; Mallarddy, A.; Kumar, B. A.;
Raju, P.; Gopal, J. V.; Pushpavalli, S. N. C. V. L.; Lavanya, A.;
Sarma, P. Bioorg. Med. Chem. 2011,19, 4589-4600. cited by applicant
.
Kumar, A.; Alegria, A. E. J. Heterocycl. Chem. 2010, 47, 1275-1282.
cited by applicant .
Labruere, R.; Hautier, B.; Testud, M.; Seguin, J.; Lenoir, C.;
Desbene-Finck, S.; Helissey, P.; Garbay, C.; Chabot, G. G.; Vidal,
M.; Giorgi-Renault, S. Chern. Med. Chem., 2010, 5, 2016-2025. cited
by applicant .
Lee, C. C.; Huang, T. S. Pharm. Res. 2001,18, 846-851. cited by
applicant .
Ley, S. V.; Thomas, A. W. Angew. Chem. Intl. Ed. 2003, 42,
5400-5449. cited by applicant .
Li, W.-Q.; Wang, X.-L.; Qian, K.; Liu, Y.-Q.; Wang, C.-Y.; Yang,
L.; Tian. J.; Morris-Natschke, S. L.; Zhou, X.-W.; Lee, K.-H.
Biorg. Med. Chem. 2013, 21, 2363-2369. cited by applicant .
Marchelli, R.; Dossena, A.; Pochini, A.; Dradi, E. J. Chem. Soc.,
Perkin Trans. 1 1977, 713-717. cited by applicant .
Mider, G. B. J. Nat. Cancer Inst. 1957, 19, 191-223. cited by
applicant .
Monks, A.; Scudiero, D.; Skehan, P.; Shoemaker, R.; Paull, K.;
Vistica, D.; Hose, C.; Langley, J.; Cronise, P.; Viagro-Wolff, A.;
Gray-Goodrich, M.; Campbell, H.; Mayo, J.; Boyd, M. J. Natl. Cancer
Inst. 1991, 83, 757-766. cited by applicant .
Passarella, D.; Peretto, B.; Yepes, R. B.; Cappellettit, G.;
Cartelli, D.; Ronchi, C.; Snaith, J.; Fontana, G.; Danieli, B.;
Borlak, J. Eur. J. Med. Chem. 2010, 45, 219-226. cited by applicant
.
Pettit, G. R. J. Nat. Prod. 1995, 58, 359-364. cited by applicant
.
Pettit, G. R.; Alkalay, D. S. J. Org. Chem. 1960, 25, 1363-1365.
cited by applicant .
Pettit, G. R.; Baumann, M. F.; Rangammal, K. N. J. Med. Pharm.
Chem. 1962, 5, 800-808. cited by applicant .
Pettit, G.R et al.; Journal of Natural Products, 2016, 507-518.
cited by applicant .
Pinney, K. G.; Jelinek, C.; Edvardsen, K.; Chaplin, D. J.; Pettit,
G. R. In Anticancer Agents from Natural Products; Cragg, G. M.;
Kingston, D. G. I.; Newman, D. J.; Eds.; Taylor and Francis: Boca
Raton, FL, 2005; pp. 23-46. cited by applicant .
Rashid, M. A.; Gustafson, K. R.; Cardellina, J. H., II; Boyd, M. R.
Nat. Prod. Lett. 2000, 14, 285-292. cited by applicant .
Salerno, S.; Da Settuni, F.; Taliani, S.; Sunirubu, F.; La Motta,
C.; Fornaciari, G.; Marini, A. M. Curr. Med. Chem. 2010, 17,
4270-4290. cited by applicant .
Seliger, H. Der Krebsarzt 1955, 10, 357-360. cited by applicant
.
Singh, P.; Faridi, U.; Srivastava, S.; Kumar, J. K.; Darokar, M.P.;
Luqman, S; Shanker, K.; Chanotiya, C. S.; Gupta, A.; Gupta, M.M.;
Negi, A.N. Chem. Pharm. Bull. 2010, 58, 242-246. cited by applicant
.
Snyder, H. R.; Konecky, M. S.; Lennarz, W. J. J. Am. Chem. Soc.
1958, 80, 3611-3615. cited by applicant .
Tratrat, C.; Georgi-Renault, S.; Husson, H.-P. Org. Lett. 2002, 4,
3187-3189. cited by applicant .
Utsugi, T.; Shibata, H.; Kumio, S.; Aoyagi, K.; Wierzba, K.;
Kobunai, T.; Terada, T.; Oh-hara, T.; Tsuruo, T.; Yamada, Y. Cancer
Res. 1996, 56, 2809-2814. cited by applicant .
Wang, C.; Wu, Z.; Zhao, Y.; Ni, C.; Zhao, X.; Zhu, L. Arch. Pharm.
Chem. Life Sci. 2011, 344, 735-740. cited by applicant .
Wang, J. Z.; Tian, X.; Tsumura, H.; Shimura, K.; Ito, H. Anticancer
Drug Des. 1993, 8, 193-202. cited by applicant .
Wilstermann, A. M.; Bender, R. P.; Godfrey, M.; Choi, S.; Anklin,
C.; Berkowitz, D. B.; Osheroff, N.; Graves, D. E. Biochemistry
2007, 46, 8217-8225. cited by applicant .
Wu, Y.; Zhao, J.; Chen, J.; Pan, C.; Li, L.; Zhang, H. Org. Lett.
2009, 11, 597-600. (b) Wu, Y.; Zhang, H.; Zhao, Y.; Zhao, J.; Chen,
J.; Li, L. Org. Lett. 2007, 9, 1199-1202. cited by applicant .
Xu, H.; He, X. Q.; Bioorg. Med. Chem. Lett. 2010, 20, 4503-4506.
cited by applicant .
Yong, Y.; Shin, S. Y.; Lee, Y. H.; Lim, Y. Bioorg. Med. Chem. Lett.
2009, 19, 4367-4371. cited by applicant .
Zhang, Y.-J.; Litaudon, M.; Bousserouel, H.; Martin, M.-T.;
Thoison, O.; Leonce, S.; Dumontet, V.; Sevenet, T.; Gueritte, F. J.
Nat. Prod. 2007, 70, 1368-1370. cited by applicant .
Zhang, Z.-J.; Tian, J.; Wang, L.-T.; Wang, M.-J.; Nan, X.; Yang,
L.; Liu, Y-Q.; Morris-Natschke, S. L.; Lee, K.-H.; Biorg. Med.
Chem. 2014, 22, 204-210. cited by applicant .
Zhi, X.; Yu, X.; Yang, C.; Ding, G.; Chen, H.; Xu, H. Bioorg. Med.
Chem. Lett., 2014, 24, 765-722. cited by applicant.
|
Primary Examiner: Desai; Rita J
Attorney, Agent or Firm: Byrne Poh LLP Horan; Nina R.
Government Interests
FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
This invention was made with government support under R01 CA090441
awarded by the National Institutes of Health. The government has
certain rights in the invention.
Claims
What is claimed is:
1. A compound selected from the group consisting of:
6,7-Methylenedioxy-4-(cyclobutyl)-9-(3,4,5-trimethoxyphenyl)-4,9-dihydro--
3H-furo[3,4-b]quinolin-1-one (Compound 17);
6,7-Methylenedioxy-4-(cyclopentyl)-9-(3,4,5-trimethoxyphenyl)-4,9-dihydro-
-3H-furo[3,4-b]quinolin-1-one (Compound 18);
6,7-Methylenedioxy-4-(cyclohexyl)-9-(3,4,5-trimethoxyphenyl)-4,9-dihydro--
3H-furo[3,4-b]quinolin-1-one (Compound 19);
6,7-Methylenedioxy-4-(2-piperidin-1-yl-ethyl)-9-(3,4,5-trimethoxyphenyl)--
4,9-dihydro-3H-furo[3,4-b]quinolin-1-one (Compound 21);
6,7-Methylenedioxy-4-(2-morpholin-4-yl-ethyl)-9-(3,4,5-trimethoxyphenyl)--
4,9-dihydro-3H-furo[3,4-b]quinolin-1-one (Compound 22);
6,7-Methylenedioxy-4-(cyclopentyl)-9-(4-hydroxy-3,5-dimethoxy-phenyl)-4,9-
-dihydro-3H-furo[3,4-b]quinolin-1-one (Compound 30); and a
pharmaceutically acceptable salt thereof.
2. A pharmaceutical composition comprising a compound of claim 1 or
a pharmaceutically acceptable salt thereof and a pharmaceutically
acceptable carrier.
3. A method for treating cancer in a patient in need thereof
comprising administering to the patient a compound of claim 1,
wherein the compound is administered in an amount effective to
treat cancer.
4. The compound of claim 1, wherein the compound is selected from
the group consisting of:
6,7-Methylenedioxy-4-(cyclobutyl)-9-(3,4,5-trimethoxyphenyl)-4,9-dihydro--
3H-furo[3,4-b]quinolin-1-one (Compound 17);
6,7-Methylenedioxy-4-(cyclopentyl)-9-(3,4,5-trimethoxyphenyl)-4,9-dihydro-
-3H-furo[3,4-b]quinolin-1-one (Compound 18);
6,7-Methylenedioxy-4-(cyclohexyl)-9-(3,4,5-trimethoxyphenyl)-4,9-dihydro--
3H-furo[3,4-b]quinolin-1-one (Compound 19);
6,7-Methylenedioxy-4-(cyclopentyl)-9-(4-hydroxy-3,5-dimethoxy-phenyl)-4,9-
-dihydro-3H-furo[3,4-b]quinolin-1-one (Compound 30); and a
pharmaceutically acceptable salt thereof.
Description
BACKGROUND
The African sub-tropical medicinal plant Bridelia ferruginea Benth.
(family Euphorbiaceae) has found use in African traditional
medicine for the treatment of diarrhea, dysentery, female
sterility, and rheumatic pains. The genus contains some 60 species.
One of the early biological studies of this plant showed that crude
extracts lowered the fasting blood sugar levels of rats and
humans..sup.2 Later, more extensive studies reported in 1985.sup.3
involving the chemical composition confirmed the presence of
several already known terpenoids and flavonoids. This was followed
by the discovery of compounds thought to be responsible for the
medicinal effects of this plant such as xanthine oxidase
inhibition, related to liver disorders, and superoxide-scavenging
activity of phenolic compounds possibly related to the rheumatic
pain relief.sup.4 associated with the traditional use of B.
ferruginea. The glucoside flavonoid rutin.sup.5 was also discovered
in 1989 and thought to be the source of the hypoglycemic
effects.
As a continuation of long-term research directed at discovery and
development of new natural products with anticancer and other
biological activities, one of the co-inventors undertook an
evaluation of the B. ferruginea cancer cell growth inhibitory
constituents. Initial investigations were limited to only 3.24 g of
a dichloromethane-methanol extract but later augmented by a 34.5 kg
recollection of the dry plant. Crude extracts of B. ferruginea
displayed quite significant in vitro cancer cytostatic activity
(ED.sub.50 0.02 .mu.g/mL) in the P388 murine lymphocytic leukemia
cell line. Those results prompted an extensive P388 cell line
bioassay-guided fractionation which afforded four substantially
active cancer cell growth inhibitors, but proved to be all
previously known compounds, namely, deoxypodophyllotoxin (1),
.beta.-peltatin-5-O-.beta.-D-glucopyranoside (3a), and the indole
neoechinulin (4).
##STR00001##
While Boyd and colleagues.sup.6 had already expertly reported the
bioassay-guided fractionation of B. ferruginea extracts, the
initial sample collections were limited to a relatively small
(10-480 g).sup.6 amount of plant material. On the assumption that a
large-scale collection would lead to the isolation of active
constituents occurring at very low concentrations in this plant, we
proceeded as summarized above with a recollection of the dry plant.
Although no new cancer cell growth inhibitors were found, the
scale-up approach did provide isopicrodeoxypodophyllotoxin (2),
which is a new constituent of B. ferruginea. The scale up results
were largely consistent with those reported by the Boyd group.sup.6
in 2000, who summarized the isolation and characterization of
deoxypodophyllotoxin (1), .beta.-peltatin (3),
.beta.-peltatin-5-O-.beta.-D-glucopyranoside (3a), and
5'-demethoxy-.beta.-peltatin-5-O-.beta.-D-glucopyranoside.
By about 1955, the early research of Dr. Jonathan L. Hartwell at
the NCI had led to preclinical development of podophyllotoxin (1a)
from the dried roots and rhizomes of certain Podophyllum species,
especially the "Mayapple" (Podophyllum peltatum) used by the
Penobscot native Americans of Maine..sup.13-15 These pioneering
advances led to the present well-known anticancer drugs and lead
compounds ranging from etoposide (5) to tenoposide (6), 7, 8, 9 and
GL-331 (10)..sup.16 Indeed, until the development of taxol
(paclitaxel), etoposide, on a worldwide basis, was the most widely
prescribed anticancer drug. High-dose etoposide remains a useful
drug in combination with other small-molecule anticancer drugs for
the treatment of refractory Hodgkin's lymphoma, non-Hodgkin's
lymphoma, acute leukemia, and other refractory hematological-type
cancers..sup.17
The need for producing podophyllotoxin (1a)-derived anticancer
drugs has stimulated the exploration of other higher plant
sources,.sup.18 a number of total synthetic approaches including a
recent 12-step route (29% overall).sup.19a,b and a microbiological
approach utilizing two endophyte fungi from rhizomes of P. peltatum
that, interestingly, provided podophyllotoxin (1a), albeit in low
yield..sup.16 In parallel, a large number of attempts at successful
(simple) structural modifications of 1a have been ongoing over the
past nearly 55 years where some of the most recent appear in Ref 20
directed at anticancer,.sup.20a-i anti-insect,.sup.20j-l
antiparisitic,.sup.20k DNA damaging,.sup.201-o and vascular
disrupting.sup.20p targets. Two of the earliest arose when one of
the co-inventors began to modify the 1a aromatic system beginning
in 1958..sup.21
##STR00002## ##STR00003##
Accordingly, there is a need to provide new podophyllotoxin
compounds that have suitable cancer cell growth inhibition values
and that contain an easily derivatizable group for conjugation to
monoclonal antibodies.
Citation of any reference in this section is not to be construed as
an admission that such reference is prior art to the present
disclosure.
SUMMARY
The present disclosure relates to 4-azapodophylotoxins,
pharmaceutical compositions comprising such compounds, kits, and
methods for using such compounds or pharmaceutical compositions.
The compounds of the present disclosure contain an easily
derivatizable group for conjugation to monoclonal antibodies. The
compounds have, or are believed to have, suitable cancer cell
growth inhibition values.
In a first embodiment, the present disclosure provides a compound
of formula (I):
##STR00004##
or a pharmaceutically acceptable salt thereof, wherein
R.sub.1 is selected from H, (C.sub.1-C.sub.6)alkyl,
(C.sub.3-C.sub.7)cycloalkyl, a lone pair of electrons when N and
X.sub.1 form a double bond, or a Linker Unit;
wherein the alkyl is unsubstituted or substituted with a
substituent selected from OR.sub.10, NR.sub.10R.sub.11, (5- or
6-membered)heterocyclic ring comprising one or two heteroatoms
selected from N, O and S, (C.sub.3-C.sub.7)cycloalkyl,
(C.sub.6-C.sub.14)aryl, (5- or 6-membered)heteroaryl comprising
one, two or three heteroatoms selected from N, O and S, or a Linker
Unit;
where R.sub.10 and R.sub.11 are independently H,
(C.sub.1-C.sub.6)alkyl, a Protecting Group, or a Linker Unit;
wherein the aryl is unsubstituted or substituted with one to three
substitutents selected from halo, nitro, cyano,
(C.sub.1-C.sub.6)alkoxy, NR.sub.10R.sub.11,
(C.dbd.O)(C.sub.1-C.sub.6)alkyl, CO.sub.2R.sub.10,
CONR.sub.10R.sub.11, or a Linker Unit;
R.sub.2, R.sub.3 and R.sub.4 are independently selected from H,
(C.sub.1-C.sub.6)alkoxy, halo, OR.sub.10, or NR.sub.10R.sub.11;
R.sub.5 is H;
or R.sub.4 and R.sub.5 are taken together with the carbons to which
they are attached to form a 1,3-dioxolo ring;
R.sub.6 is selected from H or (C.sub.1-C.sub.6)alkoxy;
R.sub.7 is (C.sub.1-C.sub.6)alkoxy;
R.sub.8 is (C.sub.1-C.sub.6)alkoxy;
or R.sub.7 and R.sub.8 are taken together with the carbons to which
they are attached to form a 1,3-dioxolo ring;
R.sub.9 is H;
X.sub.1, X.sub.2 and X.sub.3 are carbon and either (a) X.sub.1 and
N form a double bond and X.sub.2 and X.sub.3 form a double bond; or
(b) X.sub.1 and X.sub.2 form a double bond.
In a second embodiment, the present disclosure provides a compound
of formula (Ia):
##STR00005##
wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6,
R.sub.7, R.sub.8 and R.sub.9 are as defined above in connection
with a compound of formula (I).
In a third embodiment, the present disclosure provides a compound
of formula (Ib):
##STR00006##
wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6,
R.sub.7, R.sub.8 and R.sub.9 are as defined above in connection
with a compound of formula (I).
DETAILED DESCRIPTION
In one or more embodiments, the compound includes the
following:
(1.) A compound of formula (I),
##STR00007##
or a pharmaceutically acceptable salt thereof, wherein
R.sub.1 is selected from H, (C.sub.1-C.sub.6)alkyl,
(C.sub.3-C.sub.7)cycloalkyl, a lone pair of electrons when N and
X.sub.1 form a double bond, or a Linker Unit;
wherein the alkyl is unsubstituted or substituted with a
substituent selected from OR.sub.10, NR.sub.10R.sub.11, (5- or
6-membered)heterocyclic ring comprising one or two heteroatoms
selected from N, O and S, (C.sub.3-C.sub.7)cycloalkyl,
(C.sub.6-C.sub.14)aryl, (5- or 6-membered)heteroaryl comprising
one, two or three heteroatoms selected from N, O and S, or a Linker
Unit;
where R.sub.10 and R.sub.11 are independently H,
(C.sub.1-C.sub.6)alkyl, a Protecting Group, or a Linker Unit;
wherein the aryl is unsubstituted or substituted with one to three
substitutents selected from halo, nitro, cyano,
(C.sub.1-C.sub.6)alkoxy, NR.sub.10R11,
(C.dbd.O)(C.sub.1-C.sub.6)alkyl, CO.sub.2R.sub.10,
CONR.sub.10R.sub.11, or a Linker Unit;
R.sub.2, R.sub.3 and R.sub.4 are independently selected from H,
(C.sub.1-C.sub.6)alkoxy, halo, OR.sub.10, or NR.sub.10R.sub.11;
R.sub.5 is H;
or R.sub.4 and R.sub.5 are taken together with the carbons to which
they are attached to form a 1,3-dioxolo ring;
R.sub.6 is selected from H or (C.sub.1-C.sub.6)alkoxy;
R.sub.7 is (C.sub.1-C.sub.6)alkoxy;
R.sub.8 is (C.sub.1-C.sub.6)alkoxy;
or R.sub.7 and R.sub.8 are taken together with the carbons to which
they are attached to form a 1,3-dioxolo ring;
R.sub.9 is H;
X.sub.1, X.sub.2 and X.sub.3 are carbon and either (a) X.sub.1 and
N form a double bond and X.sub.2 and X.sub.3 form a double
bond;
or (b) X.sub.1 and X.sub.2 form a double bond.
(2.) The compound of the above (1.), wherein
R.sub.2 is selected from H or (C.sub.1-C.sub.6)alkoxy;
R.sub.3 is selected from H, (C.sub.1-C.sub.6)alkoxy, hydroxyl,
O-Protecting Group, or O-Linker Unit;
R.sub.4 is selected from (C.sub.1-C.sub.6)alkoxy, halo, hydroxyl,
O-Protecting Group, or O-Linker Unit.
(3.) The compound of the above (1.) or the above (2.), wherein the
compound has formula (Ia)
##STR00008##
(4.) The compound of any one of the above (1.) to (3.), wherein
R.sub.1 is selected from H, (C.sub.1-C.sub.3)alkyl,
(C.sub.4-C.sub.6)cycloalkyl, a lone pair of electrons when N and
X.sub.1 form a double bond, or Linker Unit;
wherein the alkyl is unsubstituted or substituted with a
substituent selected from OR.sub.10, NR.sub.10R.sub.11, (5- or
6-membered)heterocyclic ring comprising one or two heteroatoms
selected from N, O and S, (C.sub.3-C.sub.7)cycloalkyl,
(C.sub.6-C.sub.14)aryl, (5- or 6-membered)heteroaryl comprising
one, two or three heteroatoms selected from N, O and S, or a Linker
Unit;
where R.sub.10 and R.sub.11 are independently H,
(C.sub.1-C.sub.3)alkyl, a Protecting Group, or a Linker Unit;
wherein the aryl is unsubstituted or substituted with one to three
substitutents selected from halo, nitro, cyano,
(C.sub.1-C.sub.6)alkoxy, NR.sub.10R.sub.11,
(C.dbd.O)(C.sub.1-C.sub.6)alkyl, CO.sub.2R.sub.10,
CONR.sub.10R.sub.11, or a Linker Unit;
(5.) The compound of any one of the above (1.) to (3.), wherein
R.sub.1 is (C.sub.1-C.sub.6)alkyl, wherein the alkyl is
unsubstituted or substituted with a substituent selected from
OR.sub.10, NR.sub.10R.sub.11, (5- or 6-membered)heterocyclic ring
comprising one or two heteroatoms selected from N, O and S,
(C.sub.3-C.sub.7)cycloalkyl, (C.sub.6-C.sub.14)aryl, (5- or
6-membered)heteroaryl comprising one, two or three heteroatoms
selected from N, O and S, or a Linker Unit.
(6.) The compound of the above (5.), wherein R.sub.1 is
(C.sub.1-C.sub.3)alkyl, wherein the alkyl is unsubstituted or
substituted with a substituent selected from OR.sub.10,
NR.sub.10R.sub.11, (5- or 6-membered)heterocyclic ring comprising
one or two heteroatoms selected from N, O and S,
(C.sub.3-C.sub.7)cycloalkyl, (C.sub.6-C.sub.14)aryl, (5- or
6-membered)heteroaryl comprising one, two or three heteroatoms
selected from N, O and S, or a Linker Unit.
(7.) The compound of any one of the above (1.) to (6.), wherein the
alkyl is unsubstituted.
(8.) The compound of any one of the above (1.) to (6.), wherein the
alkyl is substituted.
(9.) The compound of the above (8.), wherein the alkyl is
substituted with a substituent selected from hydroxyl,
NR.sub.10R.sub.11, piperidinyl, morpholinyl, phenyl, pyridinyl,
imidazolyl, and furyl;
wherein R.sub.10 and R.sub.11 are independently
(C.sub.1-C.sub.6)alkyl; and phenyl is unsubstituted or substituted
with a substituent selected from halo and nitro.
(10.) The compound of any one of the above (1.) to (3.), wherein
R.sub.1 is H.
(11.) The compound of any one of the above (1.) to (3.), wherein
R.sub.1 is (C.sub.4-C.sub.6)cycloalkyl.
(12.) The compound of any one of the above (1.) to (11.), wherein
R.sub.2 is selected from H or (C.sub.1-C.sub.3)alkoxy.
(13.) The compound of any one of the above (1.) to (11.), wherein
R.sub.2 is selected from H or methoxy.
(14.) The compound of the above (13.), wherein R.sub.2 is H.
(15.) The compound of the above (13.), wherein R.sub.2 is
methoxy.
(16.) The compound of any one of the above (1.) to (15.), wherein
R.sub.3 is selected from H, (C.sub.1-C.sub.3)alkoxy, hydroxyl,
O-Protecting Group, and O-Linker Unit.
(17.) The compound of any one of the above (1.) to (16.), wherein
R.sub.3 is selected from H, (C.sub.1-C.sub.3)alkoxy and
hydroxyl.
(18.) The compound of the above (17.), wherein R.sub.3 is selected
from H, methoxy and hydroxyl.
(19.) The compound of the above (17.), wherein R.sub.3H.
(20.) The compound of the above (17.), wherein R.sub.3 is
methoxy.
(21.) The compound of the above (17.), wherein R.sub.3 is
hydroxyl.
(22.) The compound of any one of the above (1.) to (21.), wherein
R.sub.4 is selected from (C.sub.1-C.sub.3)alkoxy, halo, hydroxyl,
O-Protecting Group, and O-Linker Unit.
(23.) The compound of the above (22.), wherein R.sub.4 is selected
from (C.sub.1-C.sub.3)alkoxy, halo, O-Protecting Group and
hydroxyl.
(24.) The compound of the above (22.), wherein R.sub.4 is selected
from methoxy, halo, O-Protecting Group and hydroxyl.
(25.) The compound of the above (22.), wherein R.sub.4 is
methoxy.
(26.) The compound of the above (22.), wherein R.sub.4 is halo.
(27.) The compound of the above (22.), wherein R.sub.4 is
hydroxyl.
(28.) The compound of any one of the above (1.) to (27.), wherein
R.sub.5 is H.
(29.) The compound of any one of the above (1.) to (21.), wherein
R.sub.4 and R.sub.5 are taken together with the carbons to which
they are attached to form a 1,3-dioxolo ring.
(30.) The compound of any one of the above (1.) to (29.), wherein
R.sub.6 is H or (C.sub.1-C.sub.3)alkoxy.
(31.) The compound of any one of the above (1.) to (29.), wherein
R.sub.6 is H or methoxy.
(32.) The compound of any one of the above (1.) to (29.), wherein
R.sub.6 is H.
(33.) The compound of any one of the above (1.) to (29.), wherein
R.sub.6 is methoxy.
(34.) The compound of any one of the above (1.) to (33.), wherein
R.sub.7 is (C.sub.1-C.sub.3)alkoxy.
(35.) The compound of any one of the above (1.) to (33.), wherein
R.sub.7 is methoxy.
(36.) The compound of any one of the above (1.) to (35.), wherein
R.sub.8 is (C.sub.1-C.sub.3)alkoxy.
(37.) The compound of any one of the above (1.) to (35.), wherein
R.sub.8 is methoxy.
(38.) The compound of any one of the above (1.) to (33.), wherein
R.sub.7 and R.sub.8 are taken together with the carbons to which
they are attached to form a 1,3-dioxolo ring.
(39.) The compound of the above (1.) or the above (2.), wherein the
compound has formula (Ib)
##STR00009##
(40.) The compound of the above (39.), wherein R.sub.2 is
(C.sub.1-C.sub.6)alkoxy.
(41.) The compound of the above (39.), wherein R.sub.2 is
(C.sub.1-C.sub.3)alkoxy.
(42.) The compound of the above (39.), wherein R.sub.2 is
methoxy.
(43.) The compound of any one of the above (39.) to (42.), wherein
R.sub.3 is (C.sub.1-C.sub.6)alkoxy.
(44.) The compound of any one of the above (39.) to (42.), wherein
R.sub.3 is (C.sub.1-C.sub.3)alkoxy.
(45.) The compound of any one of the above (39.) to (42.), wherein
R.sub.3 is methoxy.
(46.) The compound of any one of the above (39.) to (45.), wherein
R.sub.4 is (C.sub.1-C.sub.6)alkoxy.
(47.) The compound of any one of the above (39.) to (45.), wherein
R.sub.4 is (C.sub.1-C.sub.3)alkoxy.
(48.) The compound of any one of the above (39.) to (45.), wherein
R.sub.4 is methoxy.
(49.) The compound of any one of the above (39.) to (48.), wherein
R.sub.5 is H.
(50.) The compound of any one of the above (39.) to (49.), wherein
R.sub.6 is H.
(51.) The compound of any one of the above (39.) to (50.), wherein
R.sub.7 and R.sub.8 are taken together with the carbons to which
they are attached to form a 1,3-dioxolo ring.
(52.) A compound selected from:
6,7-Methylenedioxy-4-(2-hydroxy-ethyl)-9-(3,4,5-trimethoxyphenyl)-4,9-dih-
ydro-3H-furo[3,4-b]quinolin-1-one;
6,7-Methylenedioxy-4-(3-hydroxy-propyl)-9-(3,4,5-trimethoxyphenyl)-4,9-di-
hydro-3H-furo[3,4-b]quinolin-1-one;
6,7,8-Trimethoxy-9-(3,4,5-trimethoxyphenyl)-4,9-dihydro-3H-furo[3,4-b]qui-
nolin-1-one;
6,7,8-Trimethoxy-9-(3-bromo-4,5-trimethoxyphenyl)-4,9-dihydro-3H-furo[3,4-
-b]quinolin-1-one;
6,7,8-Trimethoxy-9-(3-OTBDMS-4-methoxyphenyl)-4,9-dihydro-3H-furo[3,4-b]q-
uinolin-1-one;
6,7,8-Trimethoxy-9-(3-hydroxy-4-methoxyphenyl)-4,9-dihydro-3H-furo[3,4-b]-
quinolin-1-one;
6,7-Methylenedioxy-9-(2,3-methylenedioxyphenyl)-4,9-dihydro-3H-furo[3,4-b-
]quinolin-1-one;
6,7-Methylenedioxy-9-(3,4,5-trimethoxyphenyl)-4,9-dihydro-3H-furo[3,4-b]q-
uinolin-1-one;
6,7-Dimethoxy-9-(3,4,5-trimethoxyphenyl)-3H-furo[3,4-b]quinolin-1-one;
6,7-Methylenedioxy-4-methyl-9-(3,4,5-trimethoxyphenyl)-4,9-dihydro-3H-fur-
o[3,4-b]quinolin-1-one;
6,7-Methylenedioxy-4-(cyclobutyl)-9-(3,4,5-trimethoxyphenyl)-4,9-dihydro--
3H-furo[3,4-b]quinolin-1-one;
6,7-Methylenedioxy-4-(cyclopentyl)-9-(3,4,5-trimethoxyphenyl)-4,9-dihydro-
-3H-furo[3,4-b]quinolin-1-one;
6,7-Methylenedioxy-4-(cyclohexyl)-9-(3,4,5-trimethoxyphenyl)-4,9-dihydro--
3H-furo[3,4-b]quinolin-1-one;
6,7-Methylenedioxy-4-(2-dimethyamino-ethyl)-9-(3,4,5-trimethoxyphenyl)-4,-
9-dihydro-3H-furo[3,4-b]quinolin-1-one;
6,7-Methylenedioxy-4-(2-piperidin-1-yl-ethyl)-9-(3,4,5-trimethoxyphenyl)--
4,9-dihydro-3H-furo[3,4-b]quinolin-1-one;
6,7-Methylenedioxy-4-(2-morpholin-4-yl-ethyl)-9-(3,4,5-trimethoxyphenyl)--
4,9-dihydro-3H-furo[3,4-b]quinolin-1-one;
6,7-Methylenedioxy-4-(4-fluoro-benzyl)-9-(3,4,5-trimethoxyphenyl)-4,9-dih-
ydro-3H-furo[3,4-b]quinolin-1-one;
6,7-Methylenedioxy-4-(2-pyridin-2-yl-ethyl)-9-(3,4,5-trimethoxyphenyl)-4,-
9-dihydro-3H-furo[3,4-b]quinolin-1-one;
6,7-Methylenedioxy-4-[2-(4-fluorophenyl)-ethyl]-9-(3,4,5-trimethoxyphenyl-
)-4,9-dihydro-3H-furo[3,4-b]quinolin-1-one;
6,7-Methylenedioxy-4-[2-(4-chlorophenyl)-ethyl]-9-(3,4,5-trimethoxyphenyl-
)-4,9-dihydro-3H-furo[3,4-b]quinolin-1-one;
6,7-Methylenedioxy-4-[2-(4-nitrophenyl)-ethyl]-9-(3,4,5-trimethoxyphenyl)-
-4,9-dihydro-3H-furo[3,4-b]quinolin-1-one;
6,7-Methylenedioxy-4-(3-imidazol-1-yl-propyl)-9-(3,4,5-trimethoxyphenyl)--
4,9-dihydro-3H-furo[3,4-b]quinolin-1-one;
6,7-Methylenedioxy-9-(4-hydroxy-3,5-dimethoxy-phenyl)-4,9-dihydro-3H-furo-
[3,4-b]quinolin-1-one;
6,7-Methylenedioxy-4-(cyclopentyl)-9-(4-hydroxy-3,5-dimethoxy-phenyl)-4,9-
-dihydro-3H-furo[3,4-b]quinolin-1-one;
6,7-Methylenedioxy-4-[2-(4-fluorophenyl)-ethyl]-9-(4-hydroxy-3,5-dimethox-
y-phenyl)-4,9-dihydro-3H-furo[3,4-b]quinolin-1-one; or
6,7-Methylenedioxy-4-(furan-2-ylmethyl)-9-(4-hydroxy-3,5-dimethoxy-phenyl-
)-4,9-dihydro-3H-furo[3,4-b]quinolin-1-one; and
a pharmaceutically acceptable salt thereof.
(53.) A compound, wherein the compound is:
##STR00010##
or a pharmaceutically acceptable salt thereof.
(54.) A compound, wherein the compound is:
##STR00011##
or a pharmaceutically acceptable salt thereof, wherein R.sub.1 is a
Linker Unit.
(55.) A compound, wherein the compound is:
##STR00012##
or a pharmaceutically acceptable salt thereof.
(56.) A compound, wherein the compound is:
##STR00013##
or a pharmaceutically acceptable salt thereof, wherein R1 is a
Linker Unit.
(57.) A compound, wherein the compound is:
##STR00014##
or a pharmaceutically acceptable salt thereof.
(58.) A compound, wherein the compound is:
##STR00015##
or a pharmaceutically acceptable salt thereof.
(59.) A compound, wherein the compound is:
##STR00016##
or a pharmaceutically acceptable salt thereof.
(60.) A compound, wherein the compound is:
##STR00017##
or a pharmaceutically acceptable salt thereof.
(61.) A compound, wherein the compound is:
##STR00018##
or a pharmaceutically acceptable salt thereof.
(62.) A compound, wherein the compound is:
##STR00019##
or a pharmaceutically acceptable salt thereof.
(63.) The compound of any one of the above (1.) to (51.), wherein
the Linker Unit comprises a cleavable linker.
(64.) The compound of the above (63.), wherein the cleavable linker
is cleavable by a method selected from the group consisting of
glycosidase-induced cleavage, acid-induced cleavage, light-induced
cleavage, peptidase-induced cleavage, esterase-induced cleavage,
and disulfide bond cleavage.
(65.) The compound of the above (63.), wherein the cleavable linker
comprises a glycosidic bond, a hydrazone, a cathepsin-B-cleavable
peptide, a disulfide or an ester bond.
(66.) The compound of the above (63.), wherein the cleavable linker
comprises glucuronide.
(67.) The compound of the above (63.), wherein the Linker Unit is
represented by formula (II): A.sub.a-W.sub.w-Y.sub.y (II),
wherein:
A is a Stretcher Unit;
a is 0 or 1,
each -W- is independently an Amino Acid Unit,
w is an integer ranging from 0 to 12,
Y is a Spacer Unit, and
y is 0, 1 or 2.
(68.) The compound of the above (67.), wherein A.sub.a is
maleimidocaproyl.
(69.) The compound of the above (67.) or (68.), wherein W.sub.w is
Valine-Citrulline.
(70.) The compound of any one of the above (67.) to (69.), wherein
Y.sub.y is p-aminobenzyloxycarbonyl.
(71.) The compound of any one of the above (63.) to (65.) and (67.)
to (70.), wherein the Linker Unit comprises a monoclonal
antibody.
(72.) A pharmaceutical composition comprising a compound of any one
of the above (1.) to (71.) or a pharmaceutically acceptable salt
thereof and a pharmaceutically acceptable carrier.
(73.) A pharmaceutical composition comprising a combination of
compounds of any one of the above (1.) to (71.) or pharmaceutically
acceptable salts thereof and a pharmaceutically acceptable
carrier.
(74.) The pharmaceutical composition of the above (72.) or (73.),
further comprising a therapeutically effective amount of
chemotherapeutic agent selected from the group consisting of a
tubulin-forming inhibitor, a topoisomerase inhibitor, and a DNA
binder.
(75.) A method for killing or inhibiting the proliferation of tumor
cells or cancer cells comprising treating tumor cells or cancer
cells with a compound of any of the above (1.) to (71.), or a
pharmaceutical composition of any one of the above (72.) to (74.),
in an amount effective to kill or inhibit the proliferation of the
tumor cells or cancer cells.
(76.) A method for treating cancer in a patient in need thereof
comprising administering to the patient a compound of any of the
above (1.) to (71.), or a pharmaceutical composition of any one of
the above (72.) to (74.), wherein the compound or pharmaceutical
composition is administered in an amount effective to treat
cancer.
(77.) The method of the above (76.), further comprising
administering an effective amount of a second therapeutic
agent.
(78.) A method of determining inhibition of cellular proliferation
by a compound, comprising contacting cells in a cell culture medium
with the compound of any of the above (1.) to (71.) and measuring
the cytotoxic activity of the compound, whereby proliferation of
the cells is inhibited.
(79.) A method of inhibiting the growth of tumor cells that
overexpress a tumor-associated antigen comprising administering to
a patient the compound of any of the above (1.) to (71.) conjugated
to an antibody that is specific for the tumor-associated antigen,
and optionally a second therapeutic agent wherein the compound and
the second therapeutic agent are each administered in amounts
effective to inhibit growth of tumor cells in the patient.
(80.) The method of the above (79.), wherein the compound
sensitizes the tumor cells to the second therapeutic agent.
(81.) The method of the above (79.), wherein the compound induces
cell death.
(82.) The method of the above (79.), wherein the compound induces
apoptosis.
(83.) The method of the above (79.), wherein the tumor cell is
selected from the group consisting of Kaposi's sarcoma, Ewing's
sarcoma, Wilms' tumor, rhabdomyosarcoma, testicular cancer,
lymphoma, Non-Hodgkin's lymphoma, Hodgkin's lymphoma, glioblastoma
multiforme, neuroblastoma, brain tumors, bone cancer, adrenal
cortex cancer, endometrium cancer, ovarian cancer, cancer of the
soft tissues, gestational trophoblastic tumors, hepatoblastoma,
cancer of the lymph system, cancers of the blood and lymph system,
multiple myeloma, myelodysplastic syndromes, retinoblastoma,
thymoma, bladder cancer, stomach cancer, uterine cancer, leukemia,
breast cancer, central nervous system cancer, lung cancer, small
cell carcinoma, squamous cell lung carcinoma, non-small cell lung
cancer, colon cancer, pancreatic cancer, and prostate cancer.
(84.) A use of the compound of any of the above (1.) to (71.) in
the manufacture of a medicament for treating cancer.
(85.) An article of manufacture comprising the compound of any of
the above (1.) to (71.), a container, and a package insert or label
indicating that the compound can be used to treat cancer
characterized by the overexpression of at least one
tumor-associated antigen.
DEFINITIONS
Unless defined otherwise, all technical and scientific terms used
herein have the same meaning as those commonly understood by one of
ordinary skill in the art to which this invention belongs. Although
methods and materials similar or equivalent to those described
herein can be used in the practice or testing of the present
disclosure, suitable methods and materials are described below. The
materials, methods and examples are illustrative only, and are not
intended to be limiting. All publications, patents and other
documents mentioned herein are incorporated by reference in their
entirety.
Throughout this specification, the word "comprise" or variations
such as "comprises" or "comprising" will be understood to imply the
inclusion of a stated integer or groups of integers but not the
exclusion of any other integer or group of integers.
The term "a" or "an" may mean more than one of an item.
The terms "and" and "or" may refer to either the conjunctive or
disjunctive and mean "and/or".
The term "about" means within plus or minus 10% of a stated value.
For example, "about 100" would refer to any number between 90 and
110.
The phrase "pharmaceutically acceptable salt," as used herein,
refers to pharmaceutically acceptable organic or inorganic salts of
a compound of the disclosure. Exemplary salts include, but are not
limited to, sulfate, citrate, acetate, oxalate, chloride, bromide,
iodide, nitrate, bisulfate, phosphate, acid phosphate,
isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate,
tannate, pantothenate, bitartrate, ascorbate, succinate, maleate,
gentisinate, fumarate, gluconate, glucuronate, saccharate, formate,
benzoate, glutamate, methanesulfonate, ethanesulfonate,
benzenesulfonate, p-toluenesulfonate, and pamoate (i.e.,
1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts.
The term "pharmaceutically acceptable carrier" refers to a diluent,
adjuvant or excipient, with which a compound of the disclosure may
be administered. Pharmaceutically acceptable carriers include any
and all solvents, diluents, or other liquid vehicles, dispersions
or suspension aids, surface active agents, isotonic agents,
thickening or emulsifying agents, preservatives, solid binders,
lubricants and the like, as suited to the particular dosage form
desired. Remington's Pharmaceutical Sciences, Sixteenth Edition, E.
W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses
various carriers used in formulating pharmaceutically acceptable
compositions and known techniques for the preparation thereof.
Except insofar as any conventional carrier medium is incompatible
with the compounds of the disclosure such as by producing any
undesirable biological effect or otherwise interacting in a
deleterious manner with any other component(s) of the
pharmaceutically acceptable composition, its use is contemplated to
be within the scope of this disclosure. Examples of
pharmaceutically acceptable carriers include, but are not limited
to, ion exchangers, alumina, aluminum stearate, lecithin, serum
proteins, such as human serum albumin, buffer substances such as
phosphates, glycine, sorbic acid, or potassium sorbate, partial
glyceride mixtures of saturated vegetable fatty acids, water, salts
or electrolytes, such as protamine sulfate, disodium hydrogen
phosphate, potassium hydrogen phosphate, sodium chloride, zinc
salts, colloidal silica, magnesium trisilicate, polyvinyl
pyrrolidone, polyacrylates, waxes,
polyethylene-polyoxypropylene-block polymers, wool fat, sugars such
as lactose, glucose and sucrose; starches such as corn starch and
potato starch; cellulose and its derivatives such as sodium
carboxymethyl cellulose, ethyl cellulose and cellulose acetate;
powdered tragacanth; malt; gelatin; talc; excipients such as cocoa
butter and suppository waxes; oils such as peanut oil, cottonseed
oil; safflower oil; sesame oil; olive oil; corn oil and soybean
oil; glycols, such a propylene glycol or polyethylene glycol;
esters, such as ethyl oleate and ethyl laurate; agar; buffering
agents such as magnesium hydroxide and aluminum hydroxide; alginic
acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl
alcohol, and phosphate buffer solutions, as well as other non-toxic
compatible lubricants such as sodium lauryl sulfate and magnesium
stearate, as well as coloring agents, releasing agents, coating
agents, sweetening, flavoring and perfuming agents, preservatives
and antioxidants can also be present in the composition, according
to the judgment of the formulator.
The term "therapeutically effective amount" refers to an amount of
a compound of the disclosure effective to treat a disease or
disorder in a patient. In the case of cancer, the therapeutically
effective amount of the compound may reduce the number of cancer
cells; reduce the tumor size; inhibit (i.e., slow to some extent
and preferably stop) cancer cell infiltration into peripheral
organs; inhibit (i.e., slow to some extent and preferably stop)
tumor metastasis; inhibit, to some extent, tumor growth; and/or
relieve to some extent one or more of the symptoms associated with
the cancer. To the extent the compound may inhibit the growth of
and/or kill existing cancer cells, it may be cytostatic and/or
cytotoxic. For cancer therapy, efficacy can, for example, be
measured by assessing the time to disease progression (TTP) and/or
determining the response rate (RR).
The terms "treat" or "treatment" refer to therapeutic treatment and
prophylactic measures to obtain a beneficial or desired result. For
purposes of this disclosure, beneficial or desired results include,
but are not limited to, alleviation of symptoms, diminishment of
extent of disease, stabilized (i.e., not worsening) state of
disease, delay or slowing of disease progression, amelioration or
palliation of the disease state, remission (whether partial or
total), whether detectable or undetectable and prevention of
relapse. "Treatment" can also include prolonging survival as
compared to expected survival if not receiving treatment. Those in
need of treatment include those already having the condition or
disorder as well as those prone to have the condition or
disorder.
In the context of cancer, the term "treating" includes any or all
of inhibiting growth of tumor cells, cancer cells, or of a tumor;
inhibiting replication of tumor cells or cancer cells, lessening of
overall tumor burden or decreasing the number of cancerous cells,
and ameliorating one or more symptoms associated with the
disease.
The term "patient," as used herein, includes, but is not limited
to, a human, rat, mouse, guinea pig, monkey, pig, goat, cow, horse,
dog, cat, bird and fowl. In some embodiments, the patient is a
human.
The terms "cancer" and "cancerous" refer to or describe the
physiological condition or disorder in mammals that is typically
characterized by unregulated cell growth. A "tumor" comprises one
or more cancerous cells.
Exemplary cancers include, but not limited to, fibrosarcoma,
myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma,
chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma,
lymphangioendotheliosarcoma, synovioma, mesothelioma, Kaposi's
sarcoma, Ewing's sarcoma, leiomyosarcoma, rhabdomyosarcoma, colon
cancer, colorectal cancer, kidney cancer, pancreatic cancer, bone
cancer, breast cancer, endometrium cancer, ovarian cancer, prostate
cancer, esophogeal cancer, stomach cancer, oral cancer, nasal
cancer, throat cancer, central nervous system cancer, squamous cell
carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland
carcinoma, sebaceous gland carcinoma, papillary carcinoma,
papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma,
bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct
carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms'
tumor, cervical cancer, uterine cancer, testicular cancer, small
cell lung carcinoma, squamous cell lung carcinoma, non-small cell
lung cancer, bladder cancer, lung cancer, epithelial carcinoma,
glioma, glioblastoma multiforme, brain tumors, astrocytoma,
medulloblastoma, craniopharyngioma, ependymoma, pinealoma,
hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma,
skin cancer, melanoma, neuroblastoma, adrenal cortex cancer,
retinoblastoma, cancer of the soft tissues, leukemia, acute
lymphoblastic leukemia (ALL), acute lymphoblastic B-cell leukemia,
acute lymphoblastic T-cell leukemia, acute myeloblastic leukemia
(AML), acute promyelocytic leukemia (APL), acute monoblastic
leukemia, acute erythroleukemic leukemia, acute megakaryoblastic
leukemia, acute myelomonocytic leukemia, acute nonlymphocyctic
leukemia, acute undifferentiated leukemia, chronic myelocytic
leukemia (CML), chronic lymphocytic leukemia (CLL), hairy cell
leukemia, multiple myeloma, Hodgkin's lymphoma, non-Hodgkin's
lymphoma, Waldenstrom's macroglobulinemia, heavy chain disease,
gestational trophoblastic tumors, hepatoblastoma, cancer of the
lymph system, cancers of the blood and lymph system,
myelodysplastic syndromes, thymoma, and polycythemia vera.
The term "cytotoxic activity" refers to a cell-killing, a
cytostatic or an anti-proliferative effect of a compound of the
disclosure. Methods for measuring cytotoxic activity are well-known
in the art. Cytotoxic activity may be expressed as the IC.sub.50
value, which is the concentration (molar or mass) per unit volume
at which half the cells survive.
The term "(C.sub.1-C.sub.6)alkyl" refers to saturated linear and
branched hydrocarbon structures having 1, 2, 3, 4, 5, or 6 carbon
atoms. When an alkyl residue having a specific number of carbons is
named, all geometric isomers having that number of carbons are
intended to be encompassed; thus, for example, "propyl" includes
n-propyl and iso-propyl and "butyl" includes n-butyl, sec-butyl,
iso-butyl and tert-butyl. Examples of (C.sub.1-C.sub.6)alkyl groups
include methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl,
n-pentyl, n-hexyl, and the like.
The term "(C.sub.1-C.sub.3)alkyl" refers to saturated linear and
branched hydrocarbon structures having 1, 2 or 3 carbon atoms. When
an alkyl residue having a specific number of carbons is named, all
geometric isomers having that number of carbons are intended to be
encompassed; thus, for example, "propyl" includes n-propyl and
iso-propyl. Examples of (C.sub.1-C.sub.3)alkyl groups include
methyl, ethyl, n-propyl and iso-propyl.
The term "(C.sub.6-C.sub.14)aryl" refers to a monovalent aromatic
hydrocarbon group which may be monocyclic, bicyclic or tricyclic,
wherein at least one ring in the system is aromatic and wherein
each ring in the system contains 3, 4, 5, 6 or 7 ring members.
Examples of (C.sub.6-C.sub.14)aryl groups include without
limitation phenyl, naphthyl, indanyl, indenyl, tetralinyl, anthryl
and phenanthryl.
The term "(5- or 6-membered)heteroaryl" refers to a monocyclic
aromatic heterocycle ring of 5 or 6 members, i.e., a monocyclic
aromatic ring comprising at least one ring heteroatom, e.g., 1, 2,
3, or 4 ring heteroatoms, each independently selected from
nitrogen, oxygen, and sulfur. A (5- or 6-membered)heteroaryl group
can be attached to the parent structure through a carbon or
heteroatom. Examples of (5- or 6-membered)heteroaryls include
pyridyl, pyrrolyl, pyrazolyl, furyl, imidazolyl, oxazolyl,
imidazolyl, thiazolyl, isoxazolyl, 1,2,3 oxadiazolyl,
1,3,4-oxadiazolyl, 1,2,5 oxadiazolyl, 1,2,3-triazolyl, pyrazolyl,
isothiazolyl, pyridazinyl, pyrimidyl, pyrazinyl, 1,2,3
thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,5
triazinyl, and thiophenyl.
The term "(5-membered)heteroaryl" refers to a monocyclic aromatic
heterocycle ring of 5 members, i.e., a monocyclic aromatic ring
comprising at least one ring heteroatom, e.g., 1, 2, 3, or 4 ring
heteroatoms, each independently selected from nitrogen, oxygen, and
sulfur. A (5-membered)heteroaryl group can be attached to the
parent structure through a carbon or heteroatom. Examples of
(5-membered)heteroaryls include pyrrolyl, pyrazolyl, furyl,
imidazolyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, 1,2,3
oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5 oxadiazolyl, 1,2,3-triazolyl,
pyrazolyl, isothiazolyl, 1,2,3 thiadiazolyl, 1,3,4-thiadiazolyl and
1,2,5-thiadiazolyl.
The term "(6-membered)heteroaryl" refers to a monocyclic aromatic
heterocycle ring of 6 members, i.e., a monocyclic aromatic ring
comprising at least one ring heteroatom, e.g., 1, 2, 3, or 4 ring
heteroatoms, each independently selected from nitrogen, oxygen, and
sulfur. A (6-membered)heteroaryl group can be attached to the
parent structure through a carbon or heteroatom. Examples of
(6-membered)heteroaryls include pyridyl, pyridazinyl, pyrimidyl,
pyrazinyl, 1,3,5 triazinyl, and thiophenyl.
The term "(C.sub.3-C.sub.7)cycloalkyl" refers to a saturated cyclic
hydrocarbon containing 3, 4, 5, 6 or 7 ring carbon atoms. Examples
of (C.sub.3-C.sub.7)cycloalkyl groups include cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
The term "(5- or 6-membered)heterocyclyl" refers to a 5- or
6-membered, saturated or partially unsaturated,
monocyclic-heterocycle containing 1, 2, or 3 ring heteroatoms, each
independently selected from nitrogen, oxygen, and sulfur, wherein
the nitrogen and sulfur heteroatoms may optionally be oxidized and
the nitrogen heteroatom may optionally be quaternized. Examples of
"(5- or 6-membered)heterocyclyl groups include pyrrolidinyl,
piperidinyl, piperazinyl, tetrahydro-oxazinyl, tetrahydrofuran,
thiolane, dithiolane, pyrroline, pyrrolidine, pyrazoline,
pyrazolidine, imidazoline, imidazolidine, tetrahydrofuranone,
.gamma.-butyrolactone, 2H-pyran, 4H-pyran, dioxolane,
tetrahydropyran, dioxane, dihydrothiophene, piperazine, morpholine,
thiomorpholine, oxazine, tetrahydro-oxazinyl, and the like.
The term "(C.sub.6)heterocycloalkyl" refers to a 6-membered,
saturated or partially unsaturated, bridged, mono- or
bicyclic-heterocycle containing 1, 2, or 3 ring heteroatoms each
independently selected from nitrogen, oxygen, and sulfur, wherein
the nitrogen and sulfur heteroatoms may optionally be oxidized and
the nitrogen heteroatom may optionally be quaternized. A
heterocycloalkyl group can be attached to the parent structure
through a carbon or heteroatom. Examples of
(C.sub.6)heterocycloalkyl groups include piperidinyl, piperazinyl,
tetrahydro-oxazinyl, tetrahydropyran, dioxane, morpholine,
thiomorpholine, and the like.
The term "amino acid" refers to both natural and unnatural amino
acids. Examples of amino acids include alanine, .beta.-alanine,
N-methyl alanine, N-ethyl alanine, N-methyl-.beta.-alanine,
N-ethyl-.beta.-alanine, arginine, asparagine, aspartic acid,
cysteine, homocysteine, cystine, glutamic acid, glutamine, glycine,
N-ethyl glycine, N-propyl glycine, N-isopropyl glycine,
phenylalanine, 4-aminophenylalanine, 3-aminophenylalanine,
2-aminophenylalanine, histidine, isoleucine, alloisoleucine,
lysine, ornithine, citrulline, leucine, norleucine, t-leucine,
methionine, proline, pipecolic acid, serine, homoserine, isoserine,
threonine, allothreonine, valine, norvaline, isovaline,
.alpha.-methylnorvaline, tryptophan, tyrosine, .gamma.-aminobutyric
acid, .delta.-aminolevulinic acid, 4-aminobenzoic acid,
.alpha.-aminoisobuyric acid, dehydroalanine, cystathionine,
lanthionine, djenkolic acid, diaminopimelic acid,
.alpha.-amino-n-heptanoic acid, .alpha.,.beta.-diaminopropionic
acid, .alpha.,.gamma.-diaminopropionic acid, .beta.-amino-n-butyric
acid, .beta.-aminoisobutyric acid, sarcosine,
.alpha.-hydroxy-.gamma.-aminobutyric acid and the like.
The term "Protecting Group" refers to any group that is capable of
reversibly protecting another functional group from undergoing an
undesired reaction. Suitable protecting groups, as well as suitable
conditions for protection and deprotection are well-known in the
art and are described e.g., in T. W. Greene and P. G. M. Wuts,
"Protective Groups in Organic Synthesis", Third edition, Wiley, New
York 1999, and references cited therein.
The term "antibody" as used herein includes whole antibodies,
monoclonal antibodies, polyclonal antibodies, monospecific
antibodies, multispecific antibodies (e.g., bispecific antibodies),
and antibody fragments that exhibit the desired biological
activity. An antibody may be of any type or class (e.g., IgG, IgE,
IgM, IgD, and IgA) or subclass (e.g., IgG1, IgG2, IgG3, IgG4, IgA1
and IgA2). The antibody may be derived from any suitable species.
In some embodiments, the antibody is of human or murine origin. An
antibody may be, for example, human, humanized or chimeric.
The term "monoclonal antibodies" as used herein refers to
antibodies produced by a single clone of cells or cell line and
comprising identical antibody molecules. The term "polyclonal
antibodies" refers to antibodies produced by more than one type of
cell or cell line and comprising different antibody molecules.
A compound of the disclosure can contain one, two, or more
asymmetric centers and thus can give rise to enantiomers,
diastereomers, and other stereoisomeric forms. The disclosure
encompasses compounds with all such possible forms, as well as
their racemic and resolved forms or any mixture thereof, unless
specifically otherwise indicated. When a compound of the disclosure
contains an olefinic double bond, a C.dbd.N double bond, or any
other center of geometric asymmetry, it is intended to include all
"geometric isomers", e.g., both Z and E geometric isomers, unless
specifically otherwise indicated. All "tautomers", e.g.,
amine-imine, enamine-enimine, enamine-imine, urea-isourea,
ketone-enol, amide-imidic acid, lactam-lactim, are intended to be
encompassed by the disclosure as well unless specifically otherwise
indicated.
Compounds of Formula (I)
In one embodiment, the present disclosure provides a compound of
formula (I),
##STR00020##
or a pharmaceutically acceptable salt thereof, wherein:
R.sub.1 is selected from H, (C.sub.1-C.sub.6)alkyl,
(C.sub.3-C.sub.7)cycloalkyl, a lone pair of electrons when N and
X.sub.1 form a double bond, or a Linker Unit;
wherein the alkyl is unsubstituted or substituted with a
substituent selected from OR.sub.10, NR.sub.10R.sub.11, (5- or
6-membered)heterocyclic ring comprising one or two heteroatoms
selected from N, O and S, (C.sub.3--C.sub.7)cycloalkyl,
(C.sub.6-C.sub.14)aryl, (5- or 6-membered)heteroaryl comprising
one, two or three heteroatoms selected from N, O and S, or a Linker
Unit;
where R.sub.10 and R.sub.11 are independently H,
(C.sub.1-C.sub.6)alkyl, a Protecting Group, or a Linker Unit;
wherein the aryl is unsubstituted or substituted with one to three
substitutents selected from halo, nitro, cyano,
(C.sub.1-C.sub.6)alkoxy, NR.sub.10R.sub.11,
(C.dbd.O)(C.sub.1-C.sub.6)alkyl, CO.sub.2R.sub.10,
CONR.sub.10R.sub.11, or a Linker Unit;
R.sub.2, R.sub.3 and R.sub.4 are independently selected from H,
(C.sub.1-C.sub.6)alkoxy, halo, OR.sub.10, or NR.sub.10R.sub.11;
R.sub.5 is H;
or R.sub.4 and R.sub.5 are taken together with the carbons to which
they are attached to form a 1,3-dioxolo ring;
R.sub.6 is selected from H or (C.sub.1-C.sub.6)alkoxy;
R.sub.7 is (C.sub.1-C.sub.6)alkoxy;
R.sub.8 is (C.sub.1-C.sub.6)alkoxy;
or R.sub.7 and R.sub.8 are taken together with the carbons to which
they are attached to form a 1,3-dioxolo ring;
R.sub.9 is H;
X.sub.1, X.sub.2 and X.sub.3 are carbon and either (a) X.sub.1 and
N form a double bond and X.sub.2 and X.sub.3 form a double bond; or
(b) X.sub.1 and X.sub.2 form a double bond.
In one embodiment, R.sub.1 is selected from H,
(C.sub.1-C.sub.6)alkyl, or (C.sub.3-C.sub.7)cycloalkyl. In another
embodiment, R.sub.1 is selected from H, (C.sub.1-C.sub.6)alkyl, or
a lone pair of electrons when N and X.sub.1 form a double bond. In
another embodiment, R1 is selected from H, (C.sub.1-C.sub.6)alkyl,
or Linker Unit. In another embodiment, R1 is selected
(C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.7)cycloalkyl, or a lone pair
of electrons when N and X.sub.1 form a double bond. n another
embodiment, R1 is selected (C.sub.1-C.sub.6)alkyl,
(C.sub.3-C.sub.7)cycloalkyl, or Linker Unit. In another embodiment,
R1 is selected from (C.sub.3-C.sub.7)cycloalkyl, a lone pair of
electrons when N and X.sub.1 form a double bond, or Linker Unit. In
embodiments of this paragraph in which R1 is
(C.sub.1-C.sub.6)alkyl, the alkyl is unsubstituted in one
embodiment and substituted in a second embodiment, wherein the
substituents are selected from OR.sub.10, NR.sub.10R.sub.11, (5- or
6-membered)heterocyclic ring comprising one or two heteroatoms
selected from N, O and S, (C.sub.3-C.sub.7)cycloalkyl,
(C.sub.6-C.sub.14)aryl, (5- or 6-membered)heteroaryl comprising
one, two or three heteroatoms selected from N, O and S, or a Linker
Unit.
In another embodiment, R1 is H. In another embodiment, R1 is
(C.sub.1-C.sub.6)alkyl. In another embodiment, R.sub.1 is methyl,
ethyl, propyl or butyl. In another embodiment, R.sub.1 is methyl,
ethyl or propyl. In another embodiment, R.sub.1 is methyl, ethyl or
butyl. In another embodiment, R.sub.1 is ethyl, propyl or butyl. In
another embodiment, R.sub.1 is methyl or ethyl. In another
embodiment, R.sub.1 is methyl or propyl. In another embodiment,
R.sub.1 is methyl or butyl. In another embodiment, R.sub.1 is ethyl
or propyl. In another embodiment, R.sub.1 is ethyl or butyl. In
another embodiment, R.sub.1 is propyl or butyl. In another
embodiment, R.sub.1 is methyl. In another embodiment, R.sub.1 is
ethyl. In another embodiment, R.sub.1 is propyl. In another
embodiment, R.sub.1 is butyl.
In one embodiment, R.sub.1 is (C.sub.1-C.sub.6)alkyl substituted
with a substituent selected from OR.sub.10, NR.sub.10R.sub.11, (5-
or 6-membered)heterocyclic ring comprising one or two heteroatoms
selected from N, O and S, (C.sub.3-C.sub.7)cycloalkyl,
(C.sub.6-C.sub.14)aryl, (5- or 6-membered)heteroaryl comprising
one, two or three heteroatoms selected from N, O and S, or a Linker
Unit. In one embodiment, the substituent is selected from OH,
N-di(C.sub.1-C.sub.6)alkyl, piperidinyl, morpholinyl, phenyl,
pyridinyl, imidazolyl, or furyl, wherein the phenyl is
unsubstituted or substituted with halo or nitro.
In one embodiment, R.sub.1 is (C.sub.3-C.sub.7)cycloalkyl. In
another embodiment, R.sub.1 is cyclopropyl, cyclobutyl, cyclopentyl
or cyclohexyl. In another embodiment, R.sub.1 is cyclopropyl,
cyclobutyl, cyclopentyl or cycloheptyl. In another embodiment,
R.sub.1 is cyclopropyl, cyclobutyl or cyclopentyl. In another
embodiment, R.sub.1 is cyclopropyl, cyclobutyl or cyclohexyl. In
another embodiment, R.sub.1 is cyclopropyl, cyclobutyl or
cycloheptyl. In another embodiment, R.sub.1 is cyclobutyl,
cyclopentyl or cyclohexyl. In another embodiment, R.sub.1 is
cyclobutyl, cyclopentyl or cycloheptyl. In another embodiment,
R.sub.1 is cyclopentyl, cyclohexyl or cycloheptyl. In another
embodiment, R.sub.1 is cyclopropyl or cyclobutyl. In another
embodiment, R.sub.1 is cyclopropyl or cyclopentyl. In another
embodiment, R.sub.1 is cyclopropyl or cyclohexyl. In another
embodiment, R.sub.1 is cyclopropyl or cycloheptyl. In another
embodiment, R.sub.1 is cyclobutyl or cyclopentyl. In another
embodiment, R.sub.1 is cyclobutyl or cyclohexyl. In another
embodiment, R.sub.1 is cyclobutyl or cycloheptyl. In another
embodiment, R.sub.1 is cyclopentyl or cyclohexyl. In another
embodiment, R.sub.1 is cyclopentyl or cycloheptyl. In another
embodiment, R.sub.1 is cyclohexyl or cycloheptyl. In another
embodiment, R.sub.1 is cyclopropyl. In another embodiment, R.sub.1
is cyclobutyl. In another embodiment, R.sub.1 is cyclopentyl. In
another embodiment, R.sub.1 is cyclohexyl. In another embodiment,
R.sub.1 is cycloheptyl.
In one embodiment, R.sub.1 is a lone pair of electrons when N and
X.sub.1 form a double bond. In another embodiment, R.sub.1 is a
Linker Unit.
In one embodiment, R.sub.2 is selected from H,
(C.sub.1-C.sub.6)alkoxy, OR.sub.10, or NR.sub.10R.sub.11. In
another embodiment, R.sub.2 is H or (C.sub.1-C.sub.6)alkoxy. In
another embodiment, R.sub.2 is H, methoxy, ethoxy or propoxy. In
another embodiment, R.sub.2 is H, methoxy or ethoxy. In another
embodiment, R.sub.2 is H, methoxy or propoxy. In another
embodiment, R.sub.2 is methoxy, ethoxy or propoxy. In another
embodiment, R.sub.2 is H or methoxy. In another embodiment, R.sub.2
is H or ethoxy. In another embodiment, R.sub.2 is H or propoxy. In
another embodiment, R.sub.2 is methoxy or ethoxy. In another
embodiment, R.sub.2 is methoxy or propoxy. In another embodiment,
R.sub.2 is ethoxy or propoxy. In another embodiment, R.sub.2 is H.
In another embodiment, R.sub.2 is (C.sub.1-C.sub.6)alkoxy. In
another embodiment, R.sub.2 is methoxy. In another embodiment,
R.sub.2 is ethoxy. In another embodiment, R.sub.2 is OR.sub.10. In
another embodiment, R.sub.2 is NR.sub.10R.sub.11.
In one embodiment, R.sub.3 is selected from H,
(C.sub.1-C.sub.6)alkoxy, OR.sub.10, or NR.sub.10R.sub.11. In
another embodiment, R.sub.3 is H, (C.sub.1-C.sub.6)alkoxy or
hydroxyl. In another embodiment, R.sub.3 is H or
(C.sub.1-C.sub.6)alkoxy. In another embodiment, R.sub.3 is H or
hydroxyl. In another embodiment, R.sub.3 is (C.sub.1-C.sub.6)alkoxy
or hydroxyl. In another embodiment, R.sub.3 is H, methoxy, ethoxy,
propoxy or hydroxyl. In another embodiment, R.sub.3 is H, methoxy
or ethoxy. In another embodiment, R.sub.3 is H, methoxy or propoxy.
In another embodiment, R.sub.3 is H, methoxy or hydroxyl. In
another embodiment, R.sub.3 is methoxy, ethoxy or propoxy. In
another embodiment, R.sub.3 is methoxy, ethoxy or hydroxyl. In
another embodiment, R.sub.3 is ethoxy, propoxy or hydroxyl. In
another embodiment, R.sub.3 is H or methoxy. In another embodiment,
R.sub.3 is H or ethoxy. In another embodiment, R.sub.3 is H or
propoxy. In another embodiment, R.sub.3 is H or hydroxyl. In
another embodiment, R.sub.3 is methoxy or ethoxy. In another
embodiment, R.sub.3 is methoxy or propoxy. In another embodiment,
R.sub.3 is methoxy or hydroxyl. In another embodiment, R.sub.3 is
ethoxy or propoxy. In another embodiment, R.sub.3 is ethoxy or
hydroxyl. In another embodiment, R.sub.3 is propoxy or hydroxyl. In
another embodiment, R.sub.3 is H. In another embodiment, R.sub.3 is
(C.sub.1-C.sub.6)alkoxy. In another embodiment, R.sub.3 is methoxy.
In another embodiment, R.sub.3 is ethoxy. In another embodiment,
R.sub.3 is OR.sub.10. In another embodiment, R.sub.3 is hydroxyl.
In another embodiment, R.sub.3 is NR.sub.10R.sub.11.
In one embodiment, R.sub.4 is H, (C.sub.1-C.sub.6)alkoxy, halo,
OR.sub.10, or NR.sub.10R.sub.11, or R.sub.4 and R.sub.5 are taken
together with the carbons to which they are attached to form a
1,3-dioxolo ring. In another embodiment, R.sub.4 is
(C.sub.1-C.sub.6)alkoxy, halo or OR.sub.10, or R.sub.4 and R.sub.5
are taken together with the carbons to which they are attached to
form a 1,3-dioxolo ring. In another embodiment, R.sub.4 is
(C.sub.1-C.sub.6)alkoxy, halo or OR.sub.10. In another embodiment,
R.sub.4 is (C.sub.1-C.sub.6)alkoxy or halo, or R.sub.4 and R.sub.5
are taken together with the carbons to which they are attached to
form a 1,3-dioxolo ring. In another embodiment, R.sub.4 is halo or
OR.sub.10, or R.sub.4 and R.sub.5 are taken together with the
carbons to which they are attached to form a 1,3-dioxolo ring. In
another embodiment, R.sub.4 is (C.sub.1-C.sub.6)alkoxy or halo. In
another embodiment, R.sub.4 is (C.sub.1-C.sub.6)alkoxy or
OR.sub.10. In another embodiment, R.sub.4 is
(C.sub.1-C.sub.6)alkoxy or NR.sub.10R.sub.11. In another
embodiment, R.sub.4 is (C.sub.1-C.sub.6)alkoxy or OR.sub.10. In
another embodiment, R.sub.4 is (C.sub.1-C.sub.6)alkoxy, or R.sub.4
and R.sub.5 are taken together with the carbons to which they are
attached to form a 1,3-dioxolo ring. In another embodiment, R.sub.4
is halo or OR.sub.10. In another embodiment, R.sub.4 is halo or
R.sub.4 and R.sub.5 are taken together with the carbons to which
they are attached to form a 1,3-dioxolo ring. In another
embodiment, R.sub.4 is OR.sub.10, or R.sub.4 and R.sub.5 are taken
together with the carbons to which they are attached to form a
1,3-dioxolo ring. In another embodiment, R.sub.4 is methoxy,
ethoxy, propoxy, bromo, fluoro, chloro, hydroxyl, or O-Protecting
Group, or R.sub.4 and R.sub.5 are taken together with the carbons
to which they are attached to form a 1,3-dioxolo ring. In another
embodiment, R.sub.4 is methoxy, bromo, hydroxyl, or O-Protecting
Group, or R.sub.4 and R.sub.5 are taken together with the carbons
to which they are attached to form a 1,3-dioxolo ring. In another
embodiment, R.sub.4 is methoxy. In another embodiment, R.sub.4 is
bromo. In another embodiment, R.sub.4 is hydroxyl. In another
embodiment, R.sub.4 is O-Protecting Group.
In one embodiment, R.sub.5 is H. In another embodiment, R.sub.4 and
R.sub.5 are taken together with the carbons to which they are
attached to form a 1,3-dioxolo ring.
In one embodiment, R.sub.6 is H. In another embodiment, R.sub.6 is
(C.sub.1-C.sub.6)alkoxy. In another embodiment, R.sub.6 is H,
methoxy, ethoxy or propoxy. In another embodiment, R.sub.6 is H,
methoxy or ethoxy. In another embodiment, R.sub.6 is H, methoxy or
propoxy. In another embodiment, R.sub.6 is methoxy, ethoxy or
propoxy. In another embodiment, R.sub.6 is H or methoxy. In another
embodiment, R.sub.6 is H or ethoxy. In another embodiment, R.sub.6
is H or propoxy. In another embodiment, R.sub.6 is methoxy or
ethoxy. In another embodiment, R.sub.6 is methoxy or propoxy. In
another embodiment, R.sub.6 is ethoxy or propoxy. In another
embodiment, R.sub.6 is methoxy. In another embodiment, R.sub.6 is
ethoxy.
In one embodiment, R.sub.7 is methoxy, ethoxy or propoxy. In
another embodiment, R.sub.7 is methoxy or ethoxy. In another
embodiment, R.sub.7 is methoxy or propoxy. In another embodiment,
R.sub.7 is ethoxy or propoxy. In another embodiment, R.sub.7 is
methoxy. In another embodiment, R.sub.7 is ethoxy.
In one embodiment, R.sub.8 is methoxy, ethoxy or propoxy. In
another embodiment, R.sub.8 is methoxy or ethoxy. In another
embodiment, R.sub.8 is methoxy or propoxy. In another embodiment,
R.sub.8 is ethoxy or propoxy. In another embodiment, R.sub.8 is
methoxy. In another embodiment, R.sub.8 is ethoxy.
In one embodiment, R.sub.7 and R.sub.8 are taken together with the
carbons to which they are attached to form a 1,3-dioxolo ring.
In one embodiment, X.sub.1, X.sub.2 and X.sub.3 are carbon and
X.sub.1 and N form a double bond and X.sub.2 and X.sub.3 form a
double bond. In another embodiment, X.sub.1, X.sub.2 and X.sub.3
are carbon and X.sub.1 and X.sub.2 form a double bond. In one
embodiment, R.sub.2 is selected from H or (C.sub.1-C.sub.6)alkoxy;
R.sub.3 is selected from H, (C.sub.1-C.sub.6)alkoxy, hydroxyl,
O-Protecting Group, or O-Linker Unit; and R.sub.4 is selected from
(C.sub.1-C.sub.6)alkoxy, halo, hydroxyl, O-Protecting Group, or
O-Linker Unit.
In one embodiment, the present disclosure provides a compound of
formula (Ia),
##STR00021##
or a pharmaceutically acceptable salt thereof, wherein each of
R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7,
R.sub.8 and R.sub.9 are as defined above in connection with the
compounds of formula (I).
In one embodiment, R.sub.1 is selected from H,
(C.sub.1-C.sub.6)alkyl, or (C.sub.3-C.sub.7)cycloalkyl. In another
embodiment, R.sub.1 is selected from H, (C.sub.1-C.sub.6)alkyl, or
Linker Unit. In another embodiment, R.sub.1 is selected
(C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.7)cycloalkyl, or Linker
Unit. In another embodiment, R.sub.1 is selected from
(C.sub.3-C.sub.7)cycloalkyl or Linker Unit. In embodiments of this
paragraph in which R.sub.1 is (C.sub.1-C.sub.6)alkyl, the alkyl is
unsubstituted in one embodiment and substituted in a second
embodiment, wherein the substituents are selected from OR.sub.10,
NR.sub.10R.sub.11, (5- or 6-membered)heterocyclic ring comprising
one or two heteroatoms selected from N, O and S,
(C.sub.3-C.sub.7)cycloalkyl, (C.sub.6-C.sub.14)aryl, (5- or
6-membered)heteroaryl comprising one, two or three heteroatoms
selected from N, O and S, or a Linker Unit.
In another embodiment, R.sub.1 is H. In another embodiment, R.sub.1
is (C.sub.1-C.sub.6)alkyl. In another embodiment, R.sub.1 is
methyl, ethyl, propyl or butyl. In another embodiment, R.sub.1 is
methyl, ethyl or propyl. In another embodiment, R.sub.1 is methyl,
ethyl or butyl. In another embodiment, R.sub.1 is ethyl, propyl or
butyl. In another embodiment, R.sub.1 is methyl or ethyl. In
another embodiment, R.sub.1 is methyl or propyl. In another
embodiment, R.sub.1 is methyl or butyl. In another embodiment,
R.sub.1 is ethyl or propyl. In another embodiment, R.sub.1 is ethyl
or butyl. In another embodiment, R.sub.1 is propyl or butyl. In
another embodiment, R.sub.1 is methyl. In another embodiment,
R.sub.1 is ethyl. In another embodiment, R.sub.1 is propyl. In
another embodiment, R.sub.1 is butyl.
In one embodiment, R.sub.1 is (C.sub.1-C.sub.6)alkyl substituted
with a substituent selected from OR.sub.10, NR.sub.10R.sub.11, (5-
or 6-membered)heterocyclic ring comprising one or two heteroatoms
selected from N, O and S, (C.sub.3-C.sub.7)cycloalkyl,
(C.sub.6-C.sub.14)aryl, (5- or 6-membered)heteroaryl comprising
one, two or three heteroatoms selected from N, O and S, or a Linker
Unit. In one embodiment, the substituent is selected from OH,
N-di(C.sub.1-C.sub.6)alkyl, piperidinyl, morpholinyl, phenyl,
pyridinyl, imidazolyl, or furyl, wherein the phenyl is
unsubstituted or substituted with halo or nitro.
In one embodiment, R.sub.1 is (C.sub.3-C.sub.7)cycloalkyl. In
another embodiment, R.sub.1 is cyclopropyl, cyclobutyl, cyclopentyl
or cyclohexyl. In another embodiment, R.sub.1 is cyclopropyl,
cyclobutyl, cyclopentyl or cycloheptyl. In another embodiment,
R.sub.1 is cyclopropyl, cyclobutyl or cyclopentyl. In another
embodiment, R.sub.1 is cyclopropyl, cyclobutyl or cyclohexyl. In
another embodiment, R.sub.1 is cyclopropyl, cyclobutyl or
cycloheptyl. In another embodiment, R.sub.1 is cyclobutyl,
cyclopentyl or cyclohexyl. In another embodiment, R.sub.1 is
cyclobutyl, cyclopentyl or cycloheptyl. In another embodiment,
R.sub.1 is cyclopentyl, cyclohexyl or cycloheptyl. In another
embodiment, R.sub.1 is cyclopropyl or cyclobutyl. In another
embodiment, R.sub.1 is cyclopropyl or cyclopentyl. In another
embodiment, R.sub.1 is cyclopropyl or cyclohexyl. In another
embodiment, R.sub.1 is cyclopropyl or cycloheptyl. In another
embodiment, R.sub.1 is cyclobutyl or cyclopentyl. In another
embodiment, R.sub.1 is cyclobutyl or cyclohexyl. In another
embodiment, R.sub.1 is cyclobutyl or cycloheptyl. In another
embodiment, R.sub.1 is cyclopentyl or cyclohexyl. In another
embodiment, R.sub.1 is cyclopentyl or cycloheptyl. In another
embodiment, R.sub.1 is cyclohexyl or cycloheptyl. In another
embodiment, R.sub.1 is cyclopropyl. In another embodiment, R.sub.1
is cyclobutyl. In another embodiment, R.sub.1 is cyclopentyl. In
another embodiment, R.sub.1 is cyclohexyl. In another embodiment,
R.sub.1 is cycloheptyl.
In another embodiment, R.sub.1 is a Linker Unit.
In one embodiment, R.sub.2 is selected from H,
(C.sub.1-C.sub.6)alkoxy, OR.sub.10, or NR.sub.10R.sub.11. In
another embodiment, R.sub.2 is H or (C.sub.1-C.sub.6)alkoxy. In
another embodiment, R.sub.2 is H, methoxy, ethoxy or propoxy. In
another embodiment, R.sub.2 is H, methoxy or ethoxy. In another
embodiment, R.sub.2 is H, methoxy or propoxy. In another
embodiment, R.sub.2 is methoxy, ethoxy or propoxy. In another
embodiment, R.sub.2 is H or methoxy. In another embodiment, R.sub.2
is H or ethoxy. In another embodiment, R.sub.2 is H or propoxy. In
another embodiment, R.sub.2 is methoxy or ethoxy. In another
embodiment, R.sub.2 is methoxy or propoxy. In another embodiment,
R.sub.2 is ethoxy or propoxy. In another embodiment, R.sub.2 is H.
In another embodiment, R.sub.2 is (C.sub.1-C.sub.6)alkoxy. In
another embodiment, R.sub.2 is methoxy. In another embodiment,
R.sub.2 is ethoxy. In another embodiment, R.sub.2 is OR.sub.M. In
another embodiment, R.sub.2 is NR.sub.10R.sub.11.
In one embodiment, R.sub.3 is selected from H,
(C.sub.1-C.sub.6)alkoxy, OR.sub.10, or NR.sub.10R.sub.11. In
another embodiment, R.sub.3 is H, (C.sub.1-C.sub.6)alkoxy or
hydroxyl. In another embodiment, R.sub.3 is H or
(C.sub.1-C.sub.6)alkoxy. In another embodiment, R.sub.3 is H or
hydroxyl. In another embodiment, R.sub.3 is (C.sub.1-C.sub.6)alkoxy
or hydroxyl. In another embodiment, R.sub.3 is H, methoxy, ethoxy,
propoxy or hydroxyl. In another embodiment, R.sub.3 is H, methoxy
or ethoxy. In another embodiment, R.sub.3 is H, methoxy or propoxy.
In another embodiment, R.sub.3 is H, methoxy or hydroxyl. In
another embodiment, R.sub.3 is methoxy, ethoxy or propoxy. In
another embodiment, R.sub.3 is methoxy, ethoxy or hydroxyl. In
another embodiment, R.sub.3 is ethoxy, propoxy or hydroxyl. In
another embodiment, R.sub.3 is H or methoxy. In another embodiment,
R.sub.3 is H or ethoxy. In another embodiment, R.sub.3 is H or
propoxy. In another embodiment, R.sub.3 is H or hydroxyl. In
another embodiment, R.sub.3 is methoxy or ethoxy. In another
embodiment, R.sub.3 is methoxy or propoxy. In another embodiment,
R.sub.3 is methoxy or hydroxyl. In another embodiment, R.sub.3 is
ethoxy or propoxy. In another embodiment, R.sub.3 is ethoxy or
hydroxyl. In another embodiment, R.sub.3 is propoxy or hydroxyl. In
another embodiment, R.sub.3 is H. In another embodiment, R.sub.3 is
(C.sub.1-C.sub.6)alkoxy. In another embodiment, R.sub.3 is methoxy.
In another embodiment, R.sub.3 is ethoxy. In another embodiment,
R.sub.3 is OR.sub.10. In another embodiment, R.sub.3 is hydroxyl.
In another embodiment, R.sub.3 is NR.sub.10R.sub.11.
In one embodiment, R.sub.4 is H, (C.sub.1-C.sub.6)alkoxy, halo,
OR.sub.10, or NR.sub.10R.sub.11, or R.sub.4 and R.sub.5 are taken
together with the carbons to which they are attached to form a
1,3-dioxolo ring. In another embodiment, R.sub.4 is
(C.sub.1-C.sub.6)alkoxy, halo or OR.sub.10, or R.sub.4 and R.sub.5
are taken together with the carbons to which they are attached to
form a 1,3-dioxolo ring. In another embodiment, R.sub.4 is
(C.sub.1-C.sub.6)alkoxy, halo or OR.sub.10. In another embodiment,
R.sub.4 is (C.sub.1-C.sub.6)alkoxy or halo, or R.sub.4 and R.sub.5
are taken together with the carbons to which they are attached to
form a 1,3-dioxolo ring. In another embodiment, R.sub.4 is halo or
OR.sub.10, or R.sub.4 and R.sub.5 are taken together with the
carbons to which they are attached to form a 1,3-dioxolo ring. In
another embodiment, R.sub.4 is (C.sub.1-C.sub.6)alkoxy or halo. In
another embodiment, R.sub.4 is (C.sub.1-C.sub.6)alkoxy or
OR.sub.10. In another embodiment, R.sub.4 is
(C.sub.1-C.sub.6)alkoxy or NR.sub.10R.sub.11. In another
embodiment, R.sub.4 is (C.sub.1-C.sub.6)alkoxy or OR.sub.10. In
another embodiment, R.sub.4 is (C.sub.1-C.sub.6)alkoxy, or R.sub.4
and R.sub.5 are taken together with the carbons to which they are
attached to form a 1,3-dioxolo ring. In another embodiment, R.sub.4
is halo or OR.sub.10. In another embodiment, R.sub.4 is halo or
R.sub.4 and R.sub.5 are taken together with the carbons to which
they are attached to form a 1,3-dioxolo ring. In another
embodiment, R.sub.4 is OR.sub.10, or R.sub.4 and R.sub.5 are taken
together with the carbons to which they are attached to form a
1,3-dioxolo ring. In another embodiment, R.sub.4 is methoxy,
ethoxy, propoxy, bromo, fluoro, chloro, hydroxyl, or O-Protecting
Group, or R.sub.4 and R.sub.5 are taken together with the carbons
to which they are attached to form a 1,3-dioxolo ring. In another
embodiment, R.sub.4 is methoxy, bromo, hydroxyl, or O-Protecting
Group, or R.sub.4 and R.sub.5 are taken together with the carbons
to which they are attached to form a 1,3-dioxolo ring. In another
embodiment, R.sub.4 is methoxy. In another embodiment, R.sub.4 is
bromo. In another embodiment, R.sub.4 is hydroxyl. In another
embodiment, R.sub.4 is O-Protecting Group.
In one embodiment, R.sub.5 is H. In another embodiment, R.sub.4 and
R.sub.5 are taken together with the carbons to which they are
attached to form a 1,3-dioxolo ring.
In one embodiment, R.sub.6 is H. In another embodiment, R.sub.6 is
(C.sub.1-C.sub.6)alkoxy. In another embodiment, R.sub.6 is H,
methoxy, ethoxy or propoxy. In another embodiment, R.sub.6 is H,
methoxy or ethoxy. In another embodiment, R.sub.6 is H, methoxy or
propoxy. In another embodiment, R.sub.6 is methoxy, ethoxy or
propoxy. In another embodiment, R.sub.6 is H or methoxy. In another
embodiment, R.sub.6 is H or ethoxy. In another embodiment, R.sub.6
is H or propoxy. In another embodiment, R.sub.6 is methoxy or
ethoxy. In another embodiment, R.sub.6 is methoxy or propoxy. In
another embodiment, R.sub.6 is ethoxy or propoxy. In another
embodiment, R.sub.6 is methoxy. In another embodiment, R.sub.6 is
ethoxy.
In one embodiment, R.sub.7 is methoxy, ethoxy or propoxy. In
another embodiment, R.sub.7 is methoxy or ethoxy. In another
embodiment, R.sub.7 is methoxy or propoxy. In another embodiment,
R.sub.7 is ethoxy or propoxy. In another embodiment, R.sub.7 is
methoxy. In another embodiment, R.sub.7 is ethoxy.
In one embodiment, R.sub.8 is methoxy, ethoxy or propoxy. In
another embodiment, R.sub.8 is methoxy or ethoxy. In another
embodiment, R.sub.8 is methoxy or propoxy. In another embodiment,
R.sub.8 is ethoxy or propoxy. In another embodiment, R.sub.8 is
methoxy. In another embodiment, R.sub.8 is ethoxy.
In one embodiment, R.sub.7 and R.sub.8 are taken together with the
carbons to which they are attached to form a 1,3-dioxolo ring.
In one embodiment, R.sub.2 is selected from H or
(C.sub.1-C.sub.6)alkoxy; R.sub.3 is selected from H,
(C.sub.1-C.sub.6)alkoxy, hydroxyl, O-Protecting Group, or O-Linker
Unit; and R.sub.4 is selected from (C.sub.1-C.sub.6)alkoxy, halo,
hydroxyl, O-Protecting Group, or O-Linker Unit.
In one embodiment, the present disclosure provides a compound of
formula (Ib),
##STR00022##
or a pharmaceutically acceptable salt thereof, wherein each of
R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8 and
R.sub.9 are as defined above in connection with the compounds of
formula (I).
In one embodiment, R.sub.2 is selected from H,
(C.sub.1-C.sub.6)alkoxy, OR.sub.10, or NR.sub.10R.sub.11. In
another embodiment, R.sub.2 is H or (C.sub.1-C.sub.6)alkoxy. In
another embodiment, R.sub.2 is H, methoxy, ethoxy or propoxy. In
another embodiment, R.sub.2 is H, methoxy or ethoxy. In another
embodiment, R.sub.2 is H, methoxy or propoxy. In another
embodiment, R.sub.2 is methoxy, ethoxy or propoxy. In another
embodiment, R.sub.2 is H or methoxy. In another embodiment, R.sub.2
is H or ethoxy. In another embodiment, R.sub.2 is H or propoxy. In
another embodiment, R.sub.2 is methoxy or ethoxy. In another
embodiment, R.sub.2 is methoxy or propoxy. In another embodiment,
R.sub.2 is ethoxy or propoxy. In another embodiment, R.sub.2 is H.
In another embodiment, R.sub.2 is (C.sub.1-C.sub.6)alkoxy. In
another embodiment, R.sub.2 is methoxy. In another embodiment,
R.sub.2 is ethoxy. In another embodiment, R.sub.2 is OR.sub.10. In
another embodiment, R.sub.2 is NR.sub.10R.sub.11.
In one embodiment, R.sub.3 is selected from H,
(C.sub.1-C.sub.6)alkoxy, OR.sub.10, or NR.sub.10R.sub.11. In
another embodiment, R.sub.3 is H, (C.sub.1-C.sub.6)alkoxy or
hydroxyl. In another embodiment, R.sub.3 is H or
(C.sub.1-C.sub.6)alkoxy. In another embodiment, R.sub.3 is H or
hydroxyl. In another embodiment, R.sub.3 is (C.sub.1-C.sub.6)alkoxy
or hydroxyl. In another embodiment, R.sub.3 is H, methoxy, ethoxy,
propoxy or hydroxyl. In another embodiment, R.sub.3 is H, methoxy
or ethoxy. In another embodiment, R.sub.3 is H, methoxy or propoxy.
In another embodiment, R.sub.3 is H, methoxy or hydroxyl. In
another embodiment, R.sub.3 is methoxy, ethoxy or propoxy. In
another embodiment, R.sub.3 is methoxy, ethoxy or hydroxyl. In
another embodiment, R.sub.3 is ethoxy, propoxy or hydroxyl. In
another embodiment, R.sub.3 is H or methoxy. In another embodiment,
R.sub.3 is H or ethoxy. In another embodiment, R.sub.3 is H or
propoxy. In another embodiment, R.sub.3 is H or hydroxyl. In
another embodiment, R.sub.3 is methoxy or ethoxy. In another
embodiment, R.sub.3 is methoxy or propoxy. In another embodiment,
R.sub.3 is methoxy or hydroxyl. In another embodiment, R.sub.3 is
ethoxy or propoxy. In another embodiment, R.sub.3 is ethoxy or
hydroxyl. In another embodiment, R.sub.3 is propoxy or hydroxyl. In
another embodiment, R.sub.3 is H. In another embodiment, R.sub.3 is
(C.sub.1-C.sub.6)alkoxy. In another embodiment, R.sub.3 is methoxy.
In another embodiment, R.sub.3 is ethoxy. In another embodiment,
R.sub.3 is OR.sub.10. In another embodiment, R.sub.3 is hydroxyl.
In another embodiment, R.sub.3 is NR.sub.10R.sub.11.
In one embodiment, R.sub.4 is H, (C.sub.1-C.sub.6)alkoxy, halo,
OR.sub.10, or NR.sub.10R.sub.11, or R.sub.4 and R.sub.5 are taken
together with the carbons to which they are attached to form a
1,3-dioxolo ring. In another embodiment, R.sub.4 is
(C.sub.1-C.sub.6)alkoxy, halo or OR.sub.10, or R.sub.4 and R.sub.5
are taken together with the carbons to which they are attached to
form a 1,3-dioxolo ring. In another embodiment, R.sub.4 is
(C.sub.1-C.sub.6)alkoxy, halo or OR.sub.10. In another embodiment,
R.sub.4 is (C.sub.1-C.sub.6)alkoxy or halo, or R.sub.4 and R.sub.5
are taken together with the carbons to which they are attached to
form a 1,3-dioxolo ring. In another embodiment, R.sub.4 is halo or
OR.sub.10, or R.sub.4 and R.sub.5 are taken together with the
carbons to which they are attached to form a 1,3-dioxolo ring. In
another embodiment, R.sub.4 is (C.sub.1-C.sub.6)alkoxy or halo. In
another embodiment, R.sub.4 is (C.sub.1-C.sub.6)alkoxy or
OR.sub.10. In another embodiment, R.sub.4 is
(C.sub.1-C.sub.6)alkoxy or NR.sub.10R.sub.11. In another
embodiment, R.sub.4 is (C.sub.1-C.sub.6)alkoxy or OR.sub.10. In
another embodiment, R.sub.4 is (C.sub.1-C.sub.6)alkoxy, or R.sub.4
and R.sub.5 are taken together with the carbons to which they are
attached to form a 1,3-dioxolo ring. In another embodiment, R.sub.4
is halo or OR.sub.10. In another embodiment, R.sub.4 is halo or
R.sub.4 and R.sub.5 are taken together with the carbons to which
they are attached to form a 1,3-dioxolo ring. In another
embodiment, R.sub.4 is OR.sub.10, or R.sub.4 and R.sub.5 are taken
together with the carbons to which they are attached to form a
1,3-dioxolo ring. In another embodiment, R.sub.4 is methoxy,
ethoxy, propoxy, bromo, fluoro, chloro, hydroxyl, or O-Protecting
Group, or R.sub.4 and R.sub.5 are taken together with the carbons
to which they are attached to form a 1,3-dioxolo ring. In another
embodiment, R.sub.4 is methoxy, bromo, hydroxyl, or O-Protecting
Group, or R.sub.4 and R.sub.5 are taken together with the carbons
to which they are attached to form a 1,3-dioxolo ring. In another
embodiment, R.sub.4 is methoxy. In another embodiment, R.sub.4 is
bromo. In another embodiment, R.sub.4 is hydroxyl. In another
embodiment, R.sub.4 is O-Protecting Group.
In one embodiment, R.sub.5 is H. In another embodiment, R.sub.4 and
R.sub.5 are taken together with the carbons to which they are
attached to form a 1,3-dioxolo ring.
In one embodiment, R.sub.6 is H. In another embodiment, R.sub.6 is
(C.sub.1-C.sub.6)alkoxy. In another embodiment, R.sub.6 is H,
methoxy, ethoxy or propoxy. In another embodiment, R.sub.6 is H,
methoxy or ethoxy. In another embodiment, R.sub.6 is H, methoxy or
propoxy. In another embodiment, R.sub.6 is methoxy, ethoxy or
propoxy. In another embodiment, R.sub.6 is H or methoxy. In another
embodiment, R.sub.6 is H or ethoxy. In another embodiment, R.sub.6
is H or propoxy. In another embodiment, R.sub.6 is methoxy or
ethoxy. In another embodiment, R.sub.6 is methoxy or propoxy. In
another embodiment, R.sub.6 is ethoxy or propoxy. In another
embodiment, R.sub.6 is methoxy. In another embodiment, R.sub.6 is
ethoxy.
In one embodiment, R.sub.7 is methoxy, ethoxy or propoxy. In
another embodiment, R.sub.7 is methoxy or ethoxy. In another
embodiment, R.sub.7 is methoxy or propoxy. In another embodiment,
R.sub.7 is ethoxy or propoxy. In another embodiment, R.sub.7 is
methoxy. In another embodiment, R.sub.7 is ethoxy.
In one embodiment, R.sub.8 is methoxy, ethoxy or propoxy. In
another embodiment, R.sub.8 is methoxy or ethoxy. In another
embodiment, R.sub.8 is methoxy or propoxy. In another embodiment,
R.sub.8 is ethoxy or propoxy. In another embodiment, R.sub.8 is
methoxy. In another embodiment, R.sub.8 is ethoxy.
In one embodiment, R.sub.7 and R.sub.8 are taken together with the
carbons to which they are attached to form a 1,3-dioxolo ring.
In one embodiment, R.sub.2 is selected from H or
(C.sub.1-C.sub.6)alkoxy; R.sub.3 is selected from H,
(C.sub.1-C.sub.6)alkoxy, hydroxyl, O-Protecting Group, or O-Linker
Unit; and R.sub.4 is selected from (C.sub.1-C.sub.6)alkoxy, halo,
hydroxyl, O-Protecting Group, or O-Linker Unit.
Table 1 provides representative compounds of the disclosure.
TABLE-US-00001 TABLE 1 Compound No. Structure Name 13 ##STR00023##
6,7-Methylenedioxy-4-(2- hydroxy-ethyl)-9-(3,4,5-
trimethoxyphenyl)-4,9- dihydro-3H-furo[3,4- b]quinolin-1-one 14
##STR00024## 6,7-Methylenedioxy-4-(3- hydroxy-propyl)-9-(3,4,5-
trimethoxyphenyl)-4,9- dihydro-3H-furo[3,4- b]quinolin-1-one 15
##STR00025## 6,7,8-Trimethoxy-9-(3,4,5- trimethoxyphenyl)-4,9-
dihydro-3H-furo[3,4- b]quinolin-1-one .sup. 15a ##STR00026##
6,7,8-Trimethoxy-9-(3- bromo-4,5- trimethoxyphenyl)-4,9-
dihydro-3H-furo[3,4- b]quinolin-1-one 15b ##STR00027##
6,7,8-Trimethoxy-9-(3- OTBDMS-4-methoxyphenyl)-
4,9-dihydro-3H-furo[3,4- b]quinolin-1-one .sup. 15c ##STR00028##
6,7,8-Trimethoxy-9-(3- hydroxy-4-methoxyphenyl)-
4,9-dihydro-3H-furo[3,4- b]quinolin-1-one 15d ##STR00029##
6,7-Methylenedioxy-9-(2,3- methylenedioxyphenyl)-4,9-
dihydro-3H-furo[3,4- b]quinolin-1-one .sup. 15e ##STR00030##
6,7-Methylenedioxy-9-(3,4,5- trimethoxyphenyl)-4,9-
dihydro-3H-furo[3,4- b]quinolin-1-one .sup. 15f ##STR00031##
6,7-Dimethoxy-9-(3,4,5- trimethoxyphenyl)-3H-
furo[3,4-b]quinolin-1-one 16 ##STR00032## 6,7-Methylenedioxy-4-
methyl-9-(3,4,5- trimethoxyphenyl)-4,9- dihydro-3H-furo[3,4-
b]quinolin-1-one 17 ##STR00033## 6,7-Methylenedioxy-4-
(cyclobutyl)-9-(3,4,5- trimethoxyphenyl)-4,9- dihydro-3H-furo[3,4-
b]quinolin-1-one 18 ##STR00034## 6,7-Methylenedioxy-4-
(cyclopentyl)-9-(3,4,5- trimethoxyphenyl)-4,9- dihydro-3H-furo[3,4-
b]quinolin-1-one 19 ##STR00035## 6,7-Methylenedioxy-4-
(cyclohexyl)-9-(3,4,5- trimethoxyphenyl)-4,9- dihydro-3H-furo[3,4-
b]quinolin-1-one 20 ##STR00036## 6,7-Methylenedioxy-4-(2-
dimethyamino-ethyl)-9- (3,4,5-trimethoxyphenyl)-4,9-
dihydro-3H-furo[3,4- b]quinolin-1-one 21 ##STR00037##
6,7-Methylenedioxy-4-(2- piperidin-1-yl-ethyl)-9-(3,4,5-
trimethoxyphenyl)-4,9- dihydro-3H-furo[3,4- b]quinolin-1-one 22
##STR00038## 6,7-Methylenedioxy-4-(2- morpholin-4-yl-ethyl)-9-
(3,4,5-trimethoxyphenyl)-4,9- dihydro-3H-furo[3,4- b]quinolin-1-one
23 ##STR00039## 6,7-Methylenedioxy-4-(4- fluoro-benzyl)-9-(3,4,5-
trimethoxyphenyl)-4,9- dihydro-3H-furo[3,4- b]quinolin-1-one 24
##STR00040## 6,7-Methylenedioxy-4-(2- pyridin-2-yl-ethyl)-9-(3,4,5-
trimethoxyphenyl)-4,9- dihydro-3H-furo[3,4- b]quinolin-1-one 25
##STR00041## 6,7-Methylenedioxy-4-[2-(4-
fluorophenyl)-ethyl]-9-(3,4,5- trimethoxyphenyl)-4,9-
dihydro-3H-furo[3,4- b]quinolin-1-one 26 ##STR00042##
6,7-Methylenedioxy-4-[2-(4- chlorophenyl)-ethyl]-9-(3,4,5-
trimethoxyphenyl)-4,9- dihydro-3H-furo[3,4- b]quinolin-1-one 27
##STR00043## 6,7-Methylenedioxy-4-[2-(4-
nitrophenyl)-ethyl]-9-(3,4,5- trimethoxyphenyl)-4,9-
dihydro-3H-furo[3,4- b]quinolin-1-one 28 ##STR00044##
6,7-Methylenedioxy-4-(3- imidazol-1-yl-propyl)-9-
(3,4,5-trimethoxyphenyl)-4,9- dihydro-3H-furo[3,4- b]quinolin-1-one
29 ##STR00045## 6,7-Methylenedioxy-9-(4- hydroxy-3,5-dimethoxy-
phenyl)-4,9-dihydro-3H- furo[3,4-b]quinolin-1-one 30 ##STR00046##
6,7-Methylenedioxy-4- (cyclopentyl)-9-(4-hydroxy-
3,5-dimethoxy-phenyl)-4,9- dihydro-3H-furo[3,4- b]quinolin-1-one 31
##STR00047## 6,7-Methylenedioxy-4-[2-(4- fluorophenyl)-ethyl]-9-(4-
hydroxy-3,5-dimethoxy- phenyl)-4,9-dihydro-3H-
furo[3,4-b]quinolin-1-one 32 ##STR00048##
6,7-Methylenedioxy-4-(furan- 2-ylmethyl)-9-(4-hydroxy-
3,5-dimethoxy-phenyl)-4,9- dihydro-3H-furo[3,4-
b]quinolin-1-one
In one or more embodiments, a compound of Table 1 is utilized as a
pharmaceutically acceptable salt thereof.
In one embodiment, the compound is selected from:
6,7-Methylenedioxy-9-(2,3-methylenedioxyphenyl)-4,9-dihydro-3H-furo[3,4-b-
]quinolin-1-one (compound 15d);
6,7-Methylenedioxy-9-(3,4,5-trimethoxyphenyl)-4,9-dihydro-3H-furo[3,4-b]q-
uinolin-1-one (compound 15e);
6,7-Methylenedioxy-4-methyl-9-(3,4,5-trimethoxyphenyl)-4,9-dihydro-3H-fur-
o[3,4-b]quinolin-1-one (compound 16);
6,7-Methylenedioxy-4-(cyclobutyl)-9-(3,4,5-trimethoxyphenyl)-4,9-dihydro--
3H-furo[3,4-b]quinolin-1-one (compound 17):
6,7-Methylenedioxy-4-(cyclopentyl)-9-(3,4,5-trimethoxyphenyl)-4,9-dihydro-
-3H-furo[3,4-b]quinolin-1-one (compound 18);
6,7-Methylenedioxy-4-(cyclohexyl)-9-(3,4,5-trimethoxyphenyl)-4,9-dihydro--
3H-furo[3,4-b]quinolin-1-one (compound 19);
6,7-Methylenedioxy-4-(4-fluoro-benzyl)-9-(3,4,5-trimethoxyphenyl)-4,9-dih-
ydro-3H-furo[3,4-b]quinolin-1-one (compound 23); or
6,7-Methylenedioxy-9-(4-hydroxy-3,5-dimethoxy-phenyl)-4,9-dihydro-3H-furo-
[3,4-b]quinolin-1-one (compound 29);
and a pharmaceutically acceptable salt thereof.
In one embodiment, the compound is selected from:
6,7-Methylenedioxy-4-methyl-9-(3,4,5-trimethoxyphenyl)-4,9-dihydro-3H-fur-
o[3,4-b]quinolin-1-one (compound 16);
6,7-Methylenedioxy-4-(cyclobutyl)-9-(3,4,5-trimethoxyphenyl)-4,9-dihydro--
3H-furo[3,4-b]quinolin-1-one (compound 17):
6,7-Methylenedioxy-4-(cyclopentyl)-9-(3,4,5-trimethoxyphenyl)-4,9-dihydro-
-3H-furo[3,4-b]quinolin-1-one (compound 18);
6,7-Methylenedioxy-4-(cyclohexyl)-9-(3,4,5-trimethoxyphenyl)-4,9-dihydro--
3H-furo[3,4-b]quinolin-1-one (compound 19);
6,7-Methylenedioxy-4-(4-fluoro-benzyl)-9-(3,4,5-trimethoxyphenyl)-4,9-dih-
ydro-3H-furo[3,4-b]quinolin-1-one (compound 23); or
6,7-Methylenedioxy-9-(4-hydroxy-3,5-dimethoxy-phenyl)-4,9-dihydro-3H-furo-
[3,4-b]quinolin-1-one (compound 29);
and a pharmaceutically acceptable salt thereof In one embodiment,
the compound is selected from:
6,7-Methylenedioxy-9-(2,3-methylenedioxyphenyl)-4,9-dihydro-3H-furo[3,4-b-
]quinolin-1-one (compound 15d); or
6,7-Methylenedioxy-9-(3,4,5-trimethoxyphenyl)-4,9-dihydro-3H-furo[3,4-b]q-
uinolin-1-one (compound 15e);
and a pharmaceutically acceptable salt thereof.
In one embodiment, the compound is conjugated to a monoclonal
antibody and the precursor compound is selected from:
6,7-Methylenedioxy-9-(2,3-methylenedioxyphenyl)-4,9-dihydro-3H-furo[3,4-b-
]quinolin-1-one (compound 15d); or
6,7-Methylenedioxy-9-(3,4,5-trimethoxyphenyl)-4,9-dihydro-3H-furo[3,4-b]q-
uinolin-1-one (compound 15e);
and a pharmaceutically acceptable salt thereof.
The compounds of this disclosure may be prepared by methods known
to those skilled in the art, methods of Schemes 1 through 3, or the
synthetic Examples set forth below.
##STR00049##
TABLE-US-00002 substrate, I R.sub.1 product, II Yield (%) 12 .sup.
##STR00050## 13 59 12a ##STR00051## 14 38 I CH.sub.3 16 53 17a
##STR00052## 17 83 18a ##STR00053## 18 54 19a ##STR00054## 19 43
20a ##STR00055## 20 52 21a ##STR00056## 21 60 22a ##STR00057## 22
68 23a ##STR00058## 23 46 24a ##STR00059## 24 39 25a ##STR00060##
25 31 26a ##STR00061## 26 30 27a ##STR00062## 27 24 28a
##STR00063## 28 10 I H 29 87 18a ##STR00064## 30 74 25a
##STR00065## 31 75 32a ##STR00066## 32 85
Initial attempts to directly add substitutions to the N-4-position
of the 4-aza-2,3-didehydro-4-deoxypodophyllotoxin skeleton were
unsuccessful. Presumably, this was due to the inactivity of the
4-nitrogen towards electrophilic attack. Indeed, the only reaction
explored that allowed the 4-aza-substitution required deprotonation
of the nitrogen using butyl lithium and subsequent alkylation with
iodomethane to yield the N-methylated product.
##STR00067##
Giorgi-Renault's short synthesis can also be utilized with
substituted secondary anilines to yield the N-substituted
derivatives, albeit in lower yields. N-Derivatives of
3,4-methylenedioxyaniline were an obvious starting point (Scheme
2), and, for example, 4-aza-alkyl derivatives 13.sup.31 and 14 were
made utilizing this route.
The prealkylated aniline route was successful in producing
4-N-alkyl derivatives. However, it was hindered by the necessity of
reducing the amide intermediates from acid chlorides or imides from
aldehydes, and its reliance on the availability of suitable
reagents. Reduction of the intermediates (cf., 11 and 11a) often
led to complex mixtures of products from incomplete reduction of
both the amide and/or ester groups.
The 4-aza substituent syntheses were improved significantly by
utilizing phenylboronic acids to arylate amines in the presence of
cupric acetate and a tertiary amine base such as triethylamine or
pyridine.sup.32 (Scheme 3). The procedure was found useful with a
wide variety of reactants. Also, many primary amines and boronic
acids are commercially available that can produce a very diverse
structural pool of arylated secondary amines. The original
report.sup.32 summarizes a variety of substrates that will react by
this procedure to form arylamines in yields ranging from 4% to
nearly quantitative with the majority of the reactions providing
yields in the 50-60% range. Several side reactions were also
experienced leading to phenols and biaryl ethers that resulted from
the boronic acid reacting with water, either present in solution or
generated in situ by triphenylboroxine formation..sup.32
##STR00068##
Compound of Formula (I) Conjugates
In some embodiments, the compound of formula (I) is conjugated
directly or indirectly to an antibody. In one embodiment, the
compound of formula (I) is conjugated directly to an antibody. In
another embodiment, the compound of formula (I) is conjugated to an
antibody through a Linker Unit. The compound may be conjugated to
an antibody through a Linker Unit at R.sub.1 in a first embodiment,
at R.sub.2 in a second embodiment, at R.sub.3 in a third embodiment
or at R.sub.4 in a fourth embodiment. The Linker Unit can operate
to provide a suitable release of the compound of formula (I). The
preparation of antibody drug conjugates is known to those of skill
in the art.
In embodiments in which the compound of formula (I) is conjugated
to an antibody through a Linker Unit, the Linker Unit may comprise
a cleavable linker in one embodiment and a non-cleavable linker in
another embodiment.
In embodiments in which the Linker Unit comprises a cleavable
linker, the cleavable linker may be cleaved by methods known in the
art. In one embodiment, the cleavable linker may be cleaved by a
method selected from the group consisting of glycosidase-induced
cleavage, acid-induced cleavage, light-induced cleavage,
peptidase-induced cleavage, esterase-induced cleavage, and
disulfide bond cleavage. In one embodiment, the cleavage method is
selected from the group consisting of glycosidase-induced cleavage,
acid-induced cleavage, peptidase-induced cleavage, esterase-induced
cleavage, and disulfide bond cleavage. In another embodiment, the
cleavage method is selected from the group consisting of
glycosidase-induced cleavage, peptidase-induced cleavage, and
esterase-induced cleavage. In another embodiment, the cleavage
method is selected from glycosidase-induced cleavage or
peptidase-induced cleavage. In another embodiment, the cleavage
method is selected from glycosidase-induced cleavage or
esterase-induced cleavage. In another embodiment, the cleavage
method is selected from peptidase-induced cleavage or
esterase-induced cleavage.
In embodiments in which the Linker Unit comprises a cleavable
linker, the cleavable linker may comprise a glycosidic bond, a
hydrazone, a cathepsin-B-cleavable peptide, a disulfide or an ester
bond. In one embodiment, the cleavable linker comprises a
glycosidic bond, a hydrazone, a cathepsin-B-cleavable peptide, or
an ester bond. In one embodiment, the cleavable linker comprises a
glycosidic bond, a hydrazone, or a cathepsin-B-cleavable peptide.
In one embodiment, the cleavable linker comprises a glycosidic
bond, a hydrazone, or an ester bond. In one embodiment, the
cleavable linker comprises a glycosidic bond, a
cathepsin-B-cleavable peptide, or an ester bond. In one embodiment,
the cleavable linker comprises a hydrazone, a cathepsin-B-cleavable
peptide, or an ester bond.
In one embodiment, the cleavable linker comprises a glycosidic
bond. In one embodiment, the cleavable linker comprises
glucuronide.
The compounds of formula (I) may be conjugated to any antibody,
e.g., an antibody that binds to a tumor associated antigen. In one
embodiment, the antibody used in the antibody drug conjugate of the
disclosure is a monoclonal antibody. In another embodiment, the
antibody used in the antibody drug conjugate of the disclosure
binds at least one of CD19, CD20, CD30, CD33, CD70, BCMA,
Glypican-3, Liv-1 and Lewis Y antigen.
When present, the Linker Unit is a bifunctional moiety that can be
used to conjugate a compound of formula (I) to an antibody. Such
bifuncitional moieties are known in the art and include, but are
not limited to, alkyldiyl, an aryldiyl, a heteroaryldiyl, moieties
such as: repeating units of alkyloxy (e.g., polyethylenoxy, PEG,
polymethyleneoxy) and alkylamino (e.g., polyethyleneamino,
Jeffamine.TM.); and diacid ester and amides including succinate,
succinamide, diglycolate, malonate, and caproamide. See, e.g., U.S.
Pat. Nos. 6,214,345 and 7,745,394, the contents of both of which
are incorporated by reference in their entireties.
In some embodiments, the Linker Unit is as described in U.S. Pat.
Nos. 6,214,345 and 7,745,394 and has formula:
A.sub.aW.sub.wY.sub.y,
wherein A is a Stretcher Unit,
a is 0 or 1,
each --W-- is independently an Amino Acid Unit,
w is an integer ranging from 0 to 12,
Y is a Spacer Unit, and
y is 0, 1 or 2.
The Stretcher Unit (-A-), when present, is capable of linking an
antibody to an Amino Acid Unit (--W--). The antibody has a
functional group that can form a bond with a functional group of a
Stretcher. Useful functional groups that can be present on an
antibody, either naturally or via chemical manipulation include,
but are not limited to, sulfhydryl, amino, hydroxyl, carboxy, the
anomeric hydroxyl group of a carbohydrate, and carboxyl. In one
aspect, the antibody functional groups are sulfhydryl and amino.
Sulfhydryl groups can be generated by reduction of an
intramolecular disulfide bond of an antibody. Alternatively,
sulfhydryl groups can be generated by reaction of an amino group of
a lysine moiety of an antibody using 2-iminothiolane (Traut's
reagent) or another sulfhydryl generating reagent.
The Amino Acid Unit (--W--), when present, links the Stretcher Unit
to the Spacer Unit if the Spacer Unit is present, links the
Stretcher Unit to the compound of formula (I) if the Spacer Unit is
absent, and links the antibody to the compound of formula (I) if
the Stretcher Unit and Spacer Unit are absent.
W.sub.W-- is a dipeptide, tripeptide, tetrapeptide, pentapeptide,
hexapeptide, heptapeptide, octapeptide, nonapeptide, decapeptide,
undecapeptide or dodecapeptide unit. The Amino Acid may be any
amino acid. In some embodiments, the Amino Acid Unit comprises
natural amino acids. In other embodiments, the Amino Acid Unit
comprises non-natural amino acids.
The Spacer Unit (--Y--), when present, links an Amino Acid Unit to
the compound of formula (I) when an Amino Acid Unit is present.
Alternately, the Spacer Unit links the Stretcher Unit to the
compound of formula (I) when the Amino Acid Unit is absent. The
Spacer Unit also links the compound of formula (I) to the antibody
when both the Amino Acid Unit and Stretcher Unit are absent.
Suitable Spacer Units include, but are not limited to a
glycine-glycine unit; a glycine unit; p-aminobenzyl alcohol (PAB)
unit or aromatic compounds that are electronically similar to the
PAB group such as 2-aminoimidazol-5-methanol derivatives (Hay et
al. (1999) Bioorg. Med. Chem. Lett. 9:2237) and ortho or
para-aminobenzylacetals; spacers that undergo cyclization upon
amide bond hydrolysis, such as substituted and unsubstituted
4-aminobutyric acid amides (Rodrigues et al., Chemistry Biology,
1995, 2, 223), appropriately substituted bicyclo[2.2.1] and
bicyclo[2.2.2] ring systems (Storm, et al., J. Amer. Chem. Soc.,
1972, 94, 5815) and 2-aminophenylpropionic acid amides (Amsberry,
et al., J. Org. Chem., 1990, 55, 5867); and a branched
bis(hydroxymethyl)styrene (BHMS) unit.
In some embodiments, the Linker Unit comprises a cleavable linker.
In some embodiments, the cleavable linker is cleavable by a method
selected from the group consisting of glycosidase-induced cleavage,
acid-induced cleavage, light-induced cleavage, peptidase-induced
cleavage, esterase-induced cleavage, and disulfide bond cleavage.
In some embodiments, the cleavable linker comprises a glycosidic
bond, a hydrazone, a cathepsin-B-cleavable peptide, a disulfide or
an ester bond. In some embodiments, the cleavable linker comprises
glucuronide.
In some embodiments, A.sub.a is maleimidocaproyl.
In some embodiments, W.sub.w is Valine-Citrulline.
In some embodiments, Y.sub.y is p-aminobenzyloxycarbonyl.
In some embodiments, A.sub.a is maleimidocaproyl, W.sub.w is
Valine-Citrulline and Y.sub.y is p-aminobenzyloxycarbonyl.
In some embodiments, the Linker Unit comprises a monoclonal
antibody.
Pharmaceutical Compositions
According to another embodiment, the present disclosure provides a
pharmaceutical composition comprising a compound described herein
or a pharmaceutically acceptable salt thereof and a
pharmaceutically acceptable carrier.
The pharmaceutical composition of the disclosure may be formulated
for administration in solid or liquid form, including those adapted
for administration by oral, nasal, parenteral, rectal, topical,
ocular, inhalation and intra-tumor administration. Parenteral
administration includes subcutaneous injections, intravenous,
intramuscular or intrasternal injection or infusion techniques. In
one embodiment, the compositions are administered parenterally. In
another embodiment, the compositions are administered
intravenously.
The pharmaceutical composition of the disclosure may be in the form
of a liquid, e.g., a solution, emulsion or suspension, pellets,
powders, sustained-release formulations, or any other form suitable
for use. The pharmaceutical composition may comprise sterile
diluents such as water, saline solution, preferably physiological
saline, Ringer's solution, isotonic sodium chloride, fixed oils
such as synthetic mono- or digylcerides, which can serve as the
solvent or suspending medium, polyethylene glycols, glycerin,
cyclodextrin, propylene glycol or other solvents; antibacterial
agents such as benzyl alcohol or methyl paraben; antioxidants such
as ascorbic acid or sodium bisulfate; chelating agents such as
ethylenediaminetetraacetic acid; buffers such as acetates,
citrates, phosphates or amino acids; agents for the adjustment of
tonicity such as sodium chloride or dextrose; surfactants;
preservatives; wetting agents; dispersing agents; suspending
agents; stabilizers; solubilizing agents; local anesthetics, e.g.,
lignocaine; or isotonic agent.
It should be understood that a specific dosage and treatment
regimen for any particular patient will depend upon a variety of
factors, including the type of patient (e.g., human), the activity
of the specific compound employed, the composition employed, the
manner of administration, the age, body weight, general health,
sex, diet, time of administration, rate of excretion, drug
combination, and the judgment of the treating physician and the
nature and the severity of the particular disorder being treated.
The amount of active ingredients will also depend upon the
particular compound in the composition. The amount of active
ingredient can be determined by standard clinical techniques. In
addition, in vitro or in vivo assays can optionally be employed to
help identify optimal dosage ranges.
Preferably, the compositions are formulated so that a dosage of
between about 0.01 to about 20 mg/kg body weight/day of the
compound of formula (I) can be administered to a patient receiving
the composition. In one embodiment, the dosage administered to the
patient is between about 0.01 mg/kg and about 10 mg/kg of the
patient's body weight. In another embodiment, the dosage
administered to the patient is between about 0.1 mg/kg and about 10
mg/kg of the patient's body weight. In yet another embodiment, the
dosage administered to the patient is between about 0.1 mg/kg and
about 5 mg/kg of the patient's body weight. In yet another
embodiment, the dosage administered is between about 0.1 mg/kg and
about 3 mg/kg of the patient's body weight. In yet another
embodiment, the dosage administered is between about 1 mg/kg and
about 3 mg/kg of the patient's body weight.
The pharmaceutical compositions comprise an effective amount of a
compound described herein such that a suitable dosage will be
obtained. Typically, this amount is at least about 0.01% of a
compound by weight of the composition. In a preferred embodiment,
pharmaceutical compositions are prepared so that a parenteral
dosage unit contains from about 0.01% to about 2% by weight of the
compound of the disclosure.
For intravenous administration, the pharmaceutical composition may
comprise from about 0.01 to about 100 mg of a compound described
herein per kg of the patient's body weight. In one aspect, the
composition may include from about 1 to about 100 mg of a compound
described herein per kg of the patient's body weight. In another
aspect, the amount administered will be in the range from about 0.1
to about 25 mg of a compound described herein per kg of body
weight.
The pharmaceutical compositions of the present disclosure may
optionally further comprise a second therapeutic agent in a
therapeutically effective amount. The second therapeutic agent
includes those that are known and those discovered to be effective
in the treatment of cancer. In some embodiments, the second
therapeutic agent is selected from the group consisting of a
tubulin-forming inhibitor, a topoisomerase inhibitor, and a DNA
binder.
Methods of Use
The present disclosure also provides methods of using the compounds
described herein or pharmaceutical compositions thereof. The
compounds and compositions are useful for killing or inhibiting the
proliferation of tumor cells or cancer cells. The compounds and
compositions are also useful for treating cancer in a patient.
In some embodiments, the present disclosure provides methods of
killing or inhibiting the proliferation of tumor cells or cancer
cells. In some embodiments, the method comprises contacting the
tumor cells or cancer cells with a compound described herein, or a
pharmaceutically acceptable salt thereof, in an amount effective to
kill or inhibit the proliferation of the tumor cells or cancer
cells. In alternate embodiments, the method comprises contacting
the tumor cells or cancer cells with a pharmaceutical composition
comprising a compound described herein in an amount effective to
kill or inhibit the proliferation of the tumor cells or cancer
cells.
In some embodiments, the method further comprises contacting the
cells with an effective amount of a second therapeutic agent or a
pharmaceutical composition thereof. In one embodiment, the second
therapeutic agent can be selected from the group consisting of a
tubulin-forming inhibitor, a topoisomerase inhibitor, and a DNA
binder.
The cells may be contacted with the compound described herein and
the second therapeutic agent simultaneously in either the same or
different compositions or sequentially in any order. The amounts of
compound described herein and the second therapeutic agent and the
relative timings of their contact will be selected in order to
achieve the desired combined effect.
In another embodiment, the present disclosure provides a method of
determining inhibition of cellular proliferation by a compound
described herein. The method comprises contacting cells in a cell
culture medium with the compound described herein and measuring the
cytotoxic activity of the compound, whereby proliferation of the
cells is inhibited. In some embodiments, the method further
comprises culturing the cells for a period from about 6 hours to
about 5 days.
Suitable cell lines are known to those skilled in the art and
include those used for evaluating other anti-cancer drugs. Such
cell lines include, but are not limited to, P388 (murine
lymphocytic leukemia); BXPC-3 (pancreas); MCF-7 (breast); SF-268
(CNS); NCI-H460 (lung); KM20L2 (colon); DU-145 (prostate); 786-O (a
renal cell carcinoma); Caki-1 (a renal cell carcinoma); L428
(Hodgkin's disease); UMRC-3 (renal cell carcinoma); LP-1 (human
myeloma); and U251 (glioblastoma cell line). In some embodiments,
the cells are obtained from a patient having a disease to be
treated (e.g., cancer) or from a relevant cell line.
In another embodiment, the present disclosure provides a method of
measuring cell viability in the presence of a compound described
herein. The method comprises contacting cells in a cell culture
medium with the compound of described herein, culturing the cells
for a period from about 6 hours to about 5 days, preferably 96
hours; and measuring cell viability. In some embodiments, the cells
are obtained from a patient having a disease to be treated (e.g.,
cancer) or from a relevant cell line.
In another embodiment, the present disclosure provides a method for
treating cancer in a patient. In some embodiments, the method
comprises administering to the patient a compound described herein,
or a pharmaceutically acceptable salt thereof, in an amount
effective to treat cancer. In other embodiments, the method
comprises administering to the patient a composition comprising a
compound described herein in an amount effective to treat
cancer.
In some embodiments, the patient receives an additional treatment,
such as radiation therapy, surgery, chemotherapy with another
chemotherapeutic agent or combinations thereof. In some
embodiments, the compound of the disclosure is administered
concurrently with the chemotherapeutic agent or with radiation
therapy or with surgery. In other embodiments, the chemotherapeutic
agent or radiation therapy or surgery is administered or performed
prior or subsequent to administration of a compound of the
disclosure.
In some embodiments, the method for treating cancer further
comprises administering to the patient an effective amount of a
second therapeutic agent, e.g., a chemotherapeutic agent. Any one
or a combination of the chemotherapeutic agents, such a standard of
care chemotherapeutic agent(s), can be administered. In some
embodiments, the chemotherapeutic agent may be selected from the
group consisting of a tubulin-forming inhibitor, a topoisomerase
inhibitor, and a DNA binder.
The compound described herein and the chemotherapeutic agent may be
administered simultaneously in either the same or different
pharmaceutical composition or sequentially in any order. The
amounts of compound described herein and the chemotherapeutic agent
and the relative timings of their administration will be selected
in order to achieve the desired combined effect.
In another embodiment, the present disclosure provides a method of
inhibiting the growth of tumor cells that overexpress a
tumor-associated antigen in a patient. In some embodiments, the
method comprises administering to the patient a compound described
herein conjugated to an antibody that is specific for the
tumor-associated antigen, wherein the compound described herein is
administered in amount effective to inhibit growth of tumor cells
in the patient. In alternate embodiments, the method comprises
administering to the patient a pharmaceutical composition
comprising a compound described herein conjugated to an antibody
that is specific for the tumor-associated antigen, wherein the
compound described herein is administered in amount effective to
inhibit growth of tumor cells in the patient. The method may
optionally further comprises administering to the patient a
chemotherapeutic agent, or a pharmaceutical composition thereof, in
an amount effective to inhibit the growth of tumor cells in the
patient.
In some embodiments, the compound sensitizes the tumor cells to the
chemotherapeutic agent.
In some embodiments, the compound induces cell death. In other
embodiments, the compound induces apoptosis.
In some embodiments, the tumor cells are associated with a cancer
selected from the group consisting of Kaposi's sarcoma, Ewing's
sarcoma, Wilms' tumor, rhabdomyosarcoma, testicular cancer,
lymphoma, Non-Hodgkin's lymphoma, Hodgkin's lymphoma, glioblastoma
multiforme, neuroblastoma, brain tumors, bone cancer, adrenal
cortex cancer, endometrium cancer, ovarian cancer, cancer of the
soft tissues, gestational trophoblastic tumors, hepatoblastoma,
cancer of the lymph system, cancers of the blood and lymph system,
multiple myeloma, myelodysplastic syndromes, retinoblastoma,
thymoma, bladder cancer, stomach cancer, uterine cancer, leukemia,
breast cancer, central nervous system cancer, lung cancer, small
cell carcinoma, squamous cell lung carcinoma, non-small cell lung
cancer, colon cancer, pancreatic cancer, and prostate cancer.
In some embodiments, the compound described herein is conjugated to
an antibody selected from the group consisting of CD19, CD20, CD30,
CD33, CD70, BCMA, Glypican-3, Liv-1 and Lewis Y.
Any compound or pharmaceutical composition described herein may be
used in the methods of the present disclosure.
In some of the above methods, the compound described herein is
administered to a patient in a composition comprising a
pharmaceutically acceptable carrier. In some of these embodiments,
the composition is administered intravenously. In certain
embodiments, the compound is formulated in a unit dosage injectable
form.
In preferred embodiments of each of the above methods, the patient
is a human.
In an additional embodiment, the present disclosure provides the
use of a compound of described herein in the manufacture of a
medicament for the treatment of any of the above mentioned cancers.
It will be appreciated that a compound described herein and one or
more second therapeutic agents may be used in the manufacture of
the medicament.
In additional embodiments, the present disclosure provides an
article of manufacture comprising a compound described herein, a
container, and a package insert or label indicating that the
compound can be used to treat cancer characterized by the
overexpression of at least one tumor-associated antigen.
The term "package insert" is used to refer to instructions
customarily included in commercial packages of therapeutic products
that contain information about the indication(s), usage, dosage,
administration, contraindications and/or warnings concerning the
use of such therapeutic products.
In order that this invention be more fully understood, the
following examples are set forth. These examples are for the
purpose of illustration only, are applicable to one or more
embodiments and are not to be construed as limiting the scope of
the invention in any way.
EXAMPLES
General Experimental Procedures. Ether refers to diethyl ether, Ar
to argon gas, sgc chromatography to silica gel column
chromatography, bac chromatography to basic alumina column
chromatography, and rt to room temperature. All solvents were
redistilled prior to use. All starting amines, copper II acetate,
and 3,4-methylenedioxyphenyl boronic acid were purchased from
Sigma-Aldrich Chemical Company. Other reagents were also purchased
from either Sigma-Aldrich Chemical Company or Acros Organics.
Reactions were monitored using thin-layer chromatography using
Analtech silica gel GHLF Uniplates visualized with long-wave (366
nm) and/or short-wave (254 nm) UV radiation and using a vapor
chamber. Solvent extracts of aqueous solutions were washed
sequentially with brine and dried over anhydrous magnesium sulfate.
Where appropriate, silica gel (70-230 mesh ASTM from Merck) or
basic alumina (150 mesh ASTM from Sigma-Aldrich) column
chromatography were used for separation of products.
Isolation of natural products was performed employing Sephadex
LH-20 gel permeation followed by partition column chromatography
with decreasing solvent polarities. Reversed-phase HPLC was
performed on a Prepex C.sub.18 column (250.times.10 mm) by
Phenomenex with a Waters Delta 600 HPLC with dual .lamda. UV
detection.
All products were recrystallized at least once before melting point
determination. Melting points are uncorrected and were determined
using an Electrothermal 9100 apparatus. The .sup.1H NMR and
.sup.13C NMR were recorded on Varian Gemini 300 MHz (.sup.1H-NMR)
and Varian Unity 400 and 500 (.sup.13C-NMR) instruments using
CDCl.sub.3, DMSO-d.sub.6, or CD.sub.3OD with the residual solvent
signals as internal references. High-resolution mass spectra were
obtained using a JEOL LCMate instrument in either FAB or APCI
modes.
Plant Material. The plant branches (34.5 kg) were collected in
Gabon, West Africa, in 1979 during the month of April. They were
identified by Dr. Arthur S. Barclay from the Medicinal Plant
Resources Laboratory, Beltsville Agricultural Research Center
(BARC)-East, Beltsville, Md.
A herbarium sample was deposited at the Economic Botany Laboratory,
Building 265, BARC-East, Beltsville, Md.
Extraction of Bridelia ferruginea. The final scale-up extraction
and isolation was prepared as follows. Branches were less than 1
inch in diameter accompanied by sawdust and were passed through a
wood chipper to increase the surface area for solvent extraction.
The chipped plant was then divided in half and placed into two 208
L drums. A 1:1 CH.sub.2Cl.sub.2--CH.sub.3OH solution was added (76
L each) to completely cover the material. The extraction was
allowed to proceed for one week. To the 1:1
CH.sub.2Cl.sub.2--CH.sub.3OH extraction solvent (30 L) removed from
the drums, H.sub.2O was added to make a final concentration of 40%
v/v H.sub.2O. The addition of H.sub.2O resulted in a partition
forming between CH.sub.2Cl.sub.2/CH.sub.3OH and
H.sub.2O/CH.sub.3OH. The CH.sub.2C.sub.12 layer was removed, and
the solvent concentrated in vacuo leaving the crude
CH.sub.2Cl.sub.2 extract. This procedure was repeated twice for
each barrel. The crude CH.sub.2Cl.sub.2 extract was then dissolved
in 9:1 CH.sub.3OH-- H.sub.2O, and partitioned with hexanes (2
L.times.3). Enough H.sub.2O was added to the 9:1
CH.sub.3OH--H.sub.2O to make a 3:2 CH.sub.3OH--H.sub.2O solution,
which was partitioned exhaustively with CH.sub.2Cl.sub.2 (1.5
L.times.5). The solvent from the hexane and CH.sub.2Cl.sub.2
partitions was separately removed and the crude fractions
collected. The 9:1 CH.sub.3OH--H.sub.2O fraction was also
collected. The murine P388 lymphocytic leukemia bioassay of the
crude fractions showed the CH.sub.2Cl.sub.2 fraction as the most
active (ED.sub.50=0.02 .mu.g/mL).
The P388 bioactivity-guided fractionation of the CH.sub.2Cl.sub.2
fraction (80 g), using a series of Sephadex LH-20 column
chromatographic separation steps with decreasing solvent polarities
(100% CH.sub.3OH.fwdarw.3:2
CH.sub.3OH--CH.sub.2Cl.sub.2.fwdarw.4:5:1
n-hexanes-EtOAc-CH.sub.3OH), led to several active fractions. A
highly P388-active fraction was subjected to semi-preparative HPLC
(gradient 25% CH.sub.3CN/H.sub.2O to 90% CH.sub.3CN/H.sub.2O) to
give deoxypodophyllotoxin (1, 10.2 mg) and
isopicrodeoxypodophyllotoxin (2, 10.4 mg) as amorphous powders.
Deoxypodophyllotoxin was present in other active fractions, and 400
mg of deoxypodophyllotoxin (1) were obtained. .beta.-Peltatin (3,
121 mg) was crystallized from another active fraction using
CH.sub.3OH-hexanes to yield a colorless crystalline solid.
.beta.-Peltatin-5-O-.beta.-D-glucopyranoside (3a) and the indole
derivative neoechinulin (4) were isolated from the CH.sub.2Cl.sub.2
partition of a 3.24 g sample of crude B. ferruginea extract,
employing a series of Sephadex LH-20 column chromatographic
separation steps with decreasing solvent polarities. Active
fractions were subjected to semi-preparative HPLC. All
spectroscopic and physical data obtained for compounds 1-4 were
consistent with literature values..sup.6-11
N-Benzo[1,3]dioxol-5-yl-oxalamic Acid Methyl Ester (11, n=0) and
N-Benzo[1,3]dioxol-5-yl-Malonamic Acid Methyl Ester (11a, n=1). A
general procedure for the synthesis of amines 11 and 11a was used
as follows, unless otherwise noted: To a stirred solution of
CH.sub.2Cl.sub.2 (100 mL), 3,4-(methylenedioxy) aniline (1 equiv.)
and triethylamine (3.0 mL), methyl chlorooxoacetate (n=0, 1 equiv.
dropwise) or methyl 3-chloro-3-oxopropionate (n=1, 1 equiv.
dropwise) was added. The solution was stirred under Ar until TLC
analysis showed that no starting material was present (18 h). Next,
the reaction mixture was washed with 1 N HCl (3.times.), and the
CH.sub.2Cl.sub.2 solution was dried and solvent was removed in
vacuo. Further product purification was accomplished using sgc
chromatography (8:1 CH.sub.2Cl.sub.2-EtOAc), followed by
recrystallization from hot EtOAc to yield esters 11 or 11a as light
yellow needles.
N-Benzo[1,3]dioxol-5-yl-oxalamic Acid Methyl Ester (11, n=0). Light
yellow needles, 5.17 g (81%). Recrystallization from hot EtOAc: mp
171-173.degree. C.; .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 8.77
(1H, bs) 7.34 (1H, d, J=2.1 Hz), 6.94 (1H, dd, J.sub.1=8.1 Hz,
J.sub.2=1.5 Hz) 6.76 (1H, d, J=8.4 Hz), 5.97 (2H, s), 3.95 (3H, s);
(+)-HRFABMS m/z 224.0550 [M+H].sup.+ (calcd for
C.sub.10H.sub.10NO.sub.5, 224.0559).
N-Benzo[1,3]dioxol-5-yl-malonamic Acid Methyl Ester (11a, n=1).
Light brown needles 6.19 g (84%). Recrystallization from hot EtOAc;
mp 165-167.degree. C.; .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.
9.09 (1H, bs), 7.24 (1H, d, J=2.1 Hz), 6.85 (1H, dd, J.sub.1=8.1
Hz, J.sub.2=2.1 Hz), 6.74 (1H, d, J=8.1 Hz), 5.94 (2H, s), 3.78
(3H, s), 3.45 (2H, s); .sup.13C NMR (CDCl.sub.3, 100 MHz) .delta.
170.37, 162.61, 147.75, 144.45, 131.62, 113.33, 108.01, 102.91,
101.25, 52.62, 41.12; (+)-HRFABMS m/z 237.9864 [M+H].sup.+ (calcd
for C.sub.11H.sub.12NO.sub.5, 238.0715).
2-(Benzo[1,3]dioxol-5-ylamino)-ethanol (12) and
3-(Benzo[1,3]dioxol-5-ylamino)-propan-1-ol (12a) (I, Scheme 2).
General procedure for the synthesis of amines 12 and 12a, unless
otherwise noted: To a stirred solution of anhydrous THF, ester 11
or 11a (1 equiv.) and LiAlH.sub.4 (1.5 equiv.) was added slowly.
The reaction proceeded for 45 min at which point TLC revealed that
no starting material was present. The reaction was terminated with
EtOAc and H.sub.2O and partitioned with EtOAc (3.times.). The
organic layers were combined and extracted with 1 N HCl solution
(3.times.). The latter aqueous extracts were combined, the pH
adjusted to 12 with 2 N KOH and extracted with CH.sub.2Cl.sub.2
(4.times.). The CH.sub.2Cl.sub.2 solution was dried and the solvent
was removed in vacuo leaving a yellow oil. Isolation of the
products was achieved with sgc chromatography (3:1 EtOAc-CH.sub.3OH
with a gradient to 100% CH.sub.3OH) to give amino alcohols 12 (n=0,
20%, 0.34 g) or 12a (n=1, 43%, 0.41 g).
2-(Benzo[1,3]dioxol-5-ylamino)-ethanol (12). Light yellow oil, 0.34
g (20%); .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 6.55 (1H, d,
J=8.1 Hz), 6.20 (1H, d, J=2.1 Hz), 6.00 (1H, dd, J.sub.1=8.7 Hz,
J.sub.2=2.7 Hz), 5.77 (2H, s), 3.72 (2H, t, J=4.8 Hz), 3.14 (2H, t,
J=5.7 Hz); .sup.13C NMR (CDCl.sub.3, 125 MHz) .delta. 148.29,
143.51, 140.08, 108.54, 105.12, 100.59, 96.59, 60.99, 47.23;
(+)-HRFABMS m/z 182.0818 [M+H].sup.+ (calcd for
C.sub.9H.sub.12NO.sub.3, 182.0817).
3-(Benzo[1,3]dioxol-5-ylamino)-propan-1-ol (12a). Light yellow oil,
0.41 g (43%). .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 6.55 (1H,
d, J=8.1 Hz), 6.18 (1H, d, J=2.1 Hz), 5.96 (1H, dd, J.sub.1=8.1 Hz,
J.sub.2=2.1 Hz), 5.76 (2H, s) 3.71 (2H, t, J=5.7 Hz), 3.12 (2H, t,
J=6 Hz), 1.77 (2H, pent., J=6 Hz); .sup.13C NMR
(CDCl.sub.3/CD.sub.3OD, 125 MHz) .delta. 148.23, 143.97, 139.79,
108.51, 104.93, 100.50, 96.38, 61.38, 43.06, 31.65; (+)-HRAPCIMS
m/z 196.0976 [M+H].sup.+ (calcd for C.sub.10H.sub.14NO.sub.3,
196.0974).
Aryl Amines 17a-32a (I, Scheme 1). General procedure for the
synthesis of component I (unless otherwise noted): To a stirred
solution prepared from CH.sub.2Cl.sub.2 (30 mL),
3,4-methylenedioxy-phenylboronic acid (0.65 g, 0.004 mol) and
Cu(II)OAc (1.15 g, 0.008 mol) was stirred for a few minutes then
triethylamine (3 mL) and the primary amine (0.004 mol) were added
(slowly). The reaction mixture was stirred under Ar for 18-48 h,
silica gel or basic alumina was added and the solvent was removed
in vacuo leaving a dry packed chromatographic substrate. The
product was isolated employing either silica gel column (sgc) or
basic alumina column (bac) chromatography to yield the necessary
aryl amines, I, which were obtained as brown oils. Maleate salts
were prepared from aryl amines in an attempt to obtain pure
compounds by crystallization. General procedure: The aryl amine was
dissolved in a small amount of ether then maleic acid in ether was
added dropwise until a cloudy solution formed. The solvent was
removed in vacuo, and the residue was recrystalized from either
EtOAc-hexanes or CH.sub.2Cl.sub.2-hexanes. Aryl amines 17a-32a (I)
were immediately used to yield dihydroquinolines 17-32 (II).
4-Aza-2,3-didehydropodophyllotoxin Modifications 13,.sup.3114,
17-32, (II, Scheme 1). General procedure for the synthesis of
quinoline II (unless otherwise noted): A stirred solution of
aniline component I (1 equiv.) in ethanol (30 mL) was heated to
reflux then 3,4,5-trimethoxybenzaldehyde (1 equiv.) and tetronic
acid (1 equiv.) were added with continued heating at reflux for 20
min to 1.5 h based upon when a TLC plate showed that a bright blue
spot was formed when viewed under UV light. The solvent was removed
in vacuo and product (II) was isolated by means of sgc
chromatography using appropriate solvent systems. Products were
often unstable and underwent degradation as evidenced by the
formation of a yellow or yellow/green compound at the baseline when
analyzed via TLC. NMR spectroscopy also showed this as an increase
of signals in the aliphatic region, not attributable to the desired
structure. Unfortunately, late in this research, extenuating
circumstances prevented further progress in this SAR study.
6,7-Methylenedioxy-4-(2-hydroxy-ethyl)-9-(3,4,5-trimethoxyphenyl)-4,9-dih-
ydro-3H-furo[3,4-b]quinolin-1-one (13). Purification:
recrystallized from CH.sub.2Cl.sub.2--CH.sub.3OH as a colorless
powder 0.485 g (59%): mp 271-273.degree. C. [lit..sup.31mp
241-243.degree. C.]; .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta.
7.15 (1H, d, J=1.8 Hz), 6.40 (1H, d, J=5.1 Hz), 6.27 (2H, s), 5.77
(1H, s), 5.75 (s, 1H), 4.83 (1H, s), 4.81 (1H, s), 4.75 (1H, s),
3.96 (2H, m), 3.63 (6H, s), 3.60 (3H, s), 3.50 (2H, m); .sup.13C
NMR (CDCl.sub.3, 100 MHz) .delta. 172.32, 160.66, 152.79, 146.90,
143.23, 143.05, 135.90, 130.70, 119.43, 109.99, 104.47, 101.35,
96.21, 94.79, 65.78, 59.82, 58.05, 55.75, 48.03, 30.68; (+)-HRFABMS
m/z 442.1519 [M+H].sup.+ (calcd for C.sub.23H.sub.23NO.sub.8,
442.1502); anal. C, 62.41; H, 5.58; N, 3.23%, calcd for
C.sub.23H.sub.23NO.sub.8, C, 62.58; H, 5.25; N, 3.17%.
6,7-Methylenedioxy-4-(3-hydroxy-propyl)-9-(3,4,5-trimethoxyphenyl)-4,9-di-
hydro-3H-furo[3,4-b]quinolin-1-one (14). Purification: sgc
chromatography (3:1 EtOAc-hexanes.fwdarw.50:1 EtOAc-CH.sub.3OH) as
off-white prisms 0.075 g (38%). Recrystallized from
CH.sub.2Cl.sub.2--CH.sub.3OH: mp 269-272.degree. C. (dec); .sup.1H
NMR (CDCl.sub.3, 400 MHz) .delta. 6.60 (1H, s), 6.51 (1H, s), 6.34
(2H, s), 5.89 (1H, s), 5.88 (1H, s), 4.95 (1H, d, J=15.6 Hz), 4.89
(1H, s), 4.76 (1H, d, J=15.7 Hz), 3.73 (9H, s), 3.63 (4H, m), 1.95
(2H, m); .sup.13C NMR (CDCl.sub.3, 100 MHz) .delta. 173.55, 158.87,
153.06, 147.49, 144.10, 141.90, 136.50, 131.16, 118.95, 110.69,
104.92, 101.54, 96.75, 95.44, 65.50, 60.65, 57.87, 55.95, 42.67,
40.74, 29.73; (+)-HRFABMS m/z 456.1657 [M+H].sup.+ (calcd for
C.sub.24H.sub.25NO.sub.8, 456.1658); anal. C, 63.05; H, 5.93; N,
3.18%, calcd for C.sub.24H.sub.25NO.sub.8, C, 63.29; H, 5.53; N,
3.08%.
Benzo[1,3]dioxol-5-yl-cyclobutyl-amine (17a). Purification: sgc
chromatography (1:1 CH.sub.2Cl.sub.2/hexanes) as light brown oil,
0.144 g (19%): .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 6.63 (1H,
d, J=8.1 Hz), 6.18 (1H, d, J=2.4 Hz), 5.98 (1H, dd, J.sub.1=8.1 Hz,
J.sub.2=2.4 Hz), 5.83 (2H, s), 3.82 (1H, m), 3.57 (1H, bs), 2.38
(2H, m), 1.78 (4H, m); .sup.13C NMR (CDCl.sub.3, 100 MHz) maleate
.delta. 168.91, 148.64, 148.10, 135.04, 128.01, 116.65, 108.75,
104.28, 102.11, 31.57, 26.49, 22.64, 14.10; (+)-HRAPCIMS m/z
192.1021 [M+H].sup.+ (calcd for C.sub.11H.sub.14NO.sub.2,
192.1025).
6,7-Methylenedioxy-4-(cyclobutyl)-9-(3,4,5-trimethoxyphenyl)-4,9-dihydro--
3H-furo[3,4-b]quinolin-1-one (17). Purification: sgc chromatography
(1:1 CH.sub.2Cl.sub.2-hexanes) as colorless powder 0.284 g (83%).
Recrystallized from EtOAc-hexanes: mp 224-226.degree. C.; .sup.1H
NMR (CDCl.sub.3, 300 MHz) .delta. 6.60 (1H, s), 6.56 (1H, s), 6.42
(2H, s), 5.95 (1H, s), 5.94 (1H, s), 4.93 (1H, d, J=15.3 Hz), 4.88
(1H, s), 4.60 (1H, d, J=15.3 Hz), 4.37 (1H, pent., J=5.3 Hz), 3.79
(9H, s), 2.69 (1H, m), 2.32 (2H, m), 2.09 (1H, m), 1.87 (2H, m);
.sup.13C NMR (CDCl.sub.3, 125 MHz) .delta. 172.25, 158.59, 153.18,
147.06, 144.15, 140.90, 136.60, 133.28, 119.46, 109.93, 103.98,
101.56, 100.73, 97.06, 66.04, 60.98, 55.96, 52.66, 40.50, 31.59,
29.36, 14.96; (+)-HRAPCIMS m/z 452.1722 [M+H].sup.+ (calcd for
C.sub.25H.sub.25NO.sub.7, 452.1709); anal C, 66.48; H, 5.83; N,
3.18%, calcd for C.sub.25H.sub.25NO.sub.7, C, 66.51; H, 5.58; N,
3.10%
Benzo[1,3]dioxol-5-yl-cyclopentylamine (18a). Purification: sgc
chromatography (10:1 CH.sub.2Cl.sub.2-EtOAc) as light tan oil,
0.314 g (40%): .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 6.55 (1H,
d, J=8.1 Hz), 6.16 (1H, d, J=2.1 Hz), 5.96 (1H, dd, J.sub.1=8.1 Hz,
J.sub.2=2.1 Hz), 5.75 (2H, s), 3.61 (1H, pent., J=5.7 Hz), 3.34
(1H, bs), 1.89 (2H, m), 1.48 (6H, m); .sup.13C NMR (CDCl.sub.3, 125
MHz) maleate .delta. 169.80, 148.50, 147.94, 135.83, 129.87,
116.96, 108.55, 104.63, 101.96, 64.70, 29.29, 23.70; (+)-HRFABMS
m/z 206.1175 [M+H].sup.+ (calcd for C.sub.12K.sub.6NO.sub.2,
206.1181).
6,7-Methylenedioxy-4-(cyclopentyl)-9-(3,4,5-trimethoxyphenyl)-4,9-dihydro-
-3H-furo[3,4-b]quinolin-1-one (18). Purification: sgc
chromatography (2:1 EtOAc-CH.sub.3OH) as colorless powder, 0.129 g
(54%). Recrystallized from EtOAc-hexanes: mp 221-223.degree. C.;
.sup.1H NMR (CDCl.sub.3, 500 MHz,) .delta. 6.64 (1H, s), 6.57 (1H,
s), 6.37 (2H, s), 5.93 (1H, s), 5.92 (1H, s), 4.93 (1H, d, J=15
Hz), 4.88 (1H, s), 4.75 (1H, d, J=15 Hz), 4.16 (1H, pent., J=8.5
Hz), 3.76 (6H, s), 3.75 (3H, s), 2.12 (2H, m), 2.00 (4H, m), 1.75
(2H, m); .sup.13C NMR (CDCl.sub.3, 125 MHz,) .delta. 172.58,
158.61, 153.12, 146.77, 143.88, 141.42, 136.58, 131.69, 119.89,
110.57, 104.41, 101.54, 99.56, 97.52, 65.85, 60.66, 60.37, 55.94,
40.68, 28.54, 28.21, 24.81, 24.78; (+)-HRAPCIMS m/z 466.1866
[M+H].sup.+ (calcd for C.sub.26H.sub.27NO.sub.7, 466.1866); anal.
C, 66.31; H, 6.09; N, 3.01%, calcd for C.sub.29H.sub.33NO.sub.8, C,
66.53; H, 6.35; N, 2.68%.
Benzo[1,3]dioxol-5-yl-cyclohexyl-amine maleate (19a). Purification:
sgc chromatography (2:1 hexanes-EtOAc) as light tan oil, 0.184 g
(23%): .sup.1H NMR (CDCl.sub.3, 400 MHz,) .delta. 7.12 (1H, s),
7.04 (1H, d, J=8 Hz), 6.75 (1H, d, J=8 Hz), 6.31 (2H, s), 5.97 (2H,
s), 3.29 (1H, m), 2.03 (2H, bd, J=11.6 Hz), 1.79 (2H, bd, J=10.4
Hz), 1.63 (1H, m), 1.49 (2H, m), 1.19 (3H, m); .sup.13C NMR
(CDCl.sub.3, 100 MHz,) maleate .delta. 169.85, 148.43, 148.04,
135.87, 128.02, 117.57, 108.45, 105.12, 101.97, 62.31, 29.02,
24.87, 24.54; (+)-HRAPCIMS m/z 220.1348 [M+H].sup.+ (calcd for
C.sub.13H.sub.18NO.sub.2, 220.1338).
6,7-Methylenedioxy-4-(cyclohexyl)-9-(3,4,5-trimethoxyphenyl)-4,9-dihydro--
3H-furo[3,4-b]quinolin-1-one (19). Purification: sgc chromatography
(1:1 EtOAc-hexanes) as light yellow powder 0.132 g (43%).
Recrystallized from EtOAc-hexanes: mp 235-237.degree. C.; .sup.1H
NMR (CDCl.sub.3, 500 MHz,) .delta. 6.67 (1H, s), 6.44 (1H, s), 6.28
(2H, s), 5.82 (1H, d, J=1 Hz), 5.81 (1H, d, J=1 Hz), 4.90 (1H, d,
J=15.3 Hz), 4.76 (1H, s), 4.67 (1H, d, J=15.3 Hz), 3.65 (9H, s),
1.83 (4H, m), 1.68 (4H, m), 1.30 (2H, m), 1.11 (1H, m); .sup.13C
NMR (CDCl.sub.3, 125 MHz) .delta. 172.35, 158.01, 153.10, 147.14,
143.91, 141.26, 136.59, 133.51, 119.73, 110.20, 104.38, 101.54,
100.63, 97.31, 66.33, 60.62, 60.25, 55.96, 40.60, 31.63, 30.89,
26.45, 26.20, 25.15; (+)-HRAPCIMS m/z 480.2020 [M+H].sup.+ (calcd
for C.sub.27H.sub.29NO.sub.7, 480.2022).
Benzo[1,3]dioxol-5-yl-N,N-dimethyl-ethane-1,2-diamine (20a).
Purification: bac chromatography (1:1 CH.sub.2Cl.sub.2-hexanes) as
light tan oil, 0.066 g (10%): .sup.1H NMR (CDCl.sub.3, 300 MHz)
.delta. 6.56 (1H, d, J=8.1 Hz), 6.17 (1H, d, J=2.4 Hz), 6.75 (1H,
dd, J.sub.1=8.1 Hz, =2.4 Hz), 5.74 (2H, s), 5.84 (2H, s), 3.07 (2H,
t, J=6.0 Hz), 2.53 (2H, t, J=6.0 Hz), 2.24 (6H, s); .sup.13C NMR
(CDCl.sub.3, 125 MHz) .delta. 148.33, 142.52, 139.85, 108.58,
104.32, 102.33, 100.51, 96.18, 57.90, 44.54; (+)-HRFABMS m/z
209.1297 [M+H].sup.+ (calcd for C.sub.11H.sub.16N.sub.2O.sub.2,
209.1290).
6,7-Methylenedioxy-4-(2-dimethyamino-ethyl)-9-(3,4,5-trimethoxyphenyl)-4,-
9-dihydro-3H-furo[3,4-b]quinolin-1-one (20). Purification: sgc
chromatography (15:1 CH.sub.2Cl.sub.2/CH.sub.3OH) as light brown
amorphous solid 0.06 g (52%). Recrystallized from CH.sub.3OH: mp
251-254.degree. C.; .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 6.57
(1H, s), 6.56 (1H, s), 6.40 (2H, s), 5.95 (1H, s), 5.94 (1H, s),
4.96 (1H, s), 4.90 (2H, s), 3.78 (9H, s), 3.60 (2H, m), 2.60 (2H,
m), 2.29 (6H, s). .sup.13C NMR (CDCl.sub.3, 125 MHz) .delta.
172.73, 158.03, 153.09, 147.53, 144.07, 141.72, 136.72, 131.27,
118.80, 110.85, 105.16, 101.57, 97.36, 95.01, 65.33, 60.66, 56.04,
45.85, 40.75; (+)-HRAPCIMS m/z 469.1976 [M+H].sup.+ (calcd for
C.sub.25H.sub.28N.sub.2O.sub.7, 469.1975).
Benzo[1,3]dioxol-5-yl-(2-piperidin-1-yl-ethyl)-1,2-diamine (21a).
Purification: bac chromatography (5:1 EtOAc-CH.sub.3OH) as brown
oil, 0.050 g (10%): .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 6.65
(1H, d, J=8.1 Hz), 6.17 (1H, d, J=2.1 Hz), 5.96 (1H, dd,
J.sub.1=8.1 Hz, J.sub.2=2.1 Hz), 5.75 (2H, s), 4.20 (1H, bs), 2.99
(2H, t, J=6.0 Hz), 2.47 (2H, t, J=6.0 Hz), 2.31 (4H, m), 1.49 (4H,
m), 1.36 (2H, m); (+)-HRFABMS m/z 249.1609 [M+H].sup.+ (calcd for
C.sub.14H.sub.20N.sub.2O.sub.2, 249.1603).
6,7-Methylenedioxy-4-(2-piperidin-1-yl-ethyl)-9-(3,4,5-trimethoxyphenyl)--
4,9-dihydro-3H-furo[3,4-b]quinolin-1-one (21). Purification: sgc
chromatography (15:1 CH.sub.2Cl.sub.2--CH.sub.3OH) as light brown
amorphous solid, 0.026 g (60%). Recrystallized from EtOAc: mp
170.degree. C. (dec); .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.
6.58 (1H, s), 6.56 (1H, s), 6.39 (2H, s), 5.95 (1H, s), 5.94 (1H,
s), 4.98 (1H, s), 4.93 (2H, s), 3.79 (9H, s), 3.65 (2H, m), 2.61
(2H, t, J=6.6 Hz), 2.45 (4H, m), 1.57 (4H, m), 1.43 (2H, m);
(+)-HRAPCIMS m/z 509.2293 [M+H].sup.+ (calcd for
C.sub.28H.sub.32N.sub.2O.sub.7, 509.2288).
Benzo[1,3]dioxol-5-yl-(2-morpholin-4-yl-ethyl)-1,2-diamine (22a).
Purification: sgc chromatography (100% CH.sub.2Cl.sub.2), light tan
oil, 0.11 g (10%); .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 6.53
(1H, d, J=8.1 Hz), 6.16 (1H, d, J=2.1 Hz), 5.94 (1H, dd, J, =8.1
Hz, J.sub.2=2.1 Hz), 5.72 (2H, s), 3.60 (4H, t, J=4.5 Hz), 2.98
(2H, t, J=5.7 Hz), 2.49 (2H, t, J=6 Hz), 2.34 (4H, m); .sup.13C NMR
(CDCl.sub.3, 125 MHz) maleate .delta. 168.55, 148.35, 141.08,
140.74, 134.02, 108.40, 105.10, 100.64, 96.69, 63.57, 55.59, 52.08,
39.11; (+)-HRAPCIMS m/z 251.1392 [M+H].sup.+ (calcd for
C.sub.13H.sub.18N.sub.2O.sub.3, 251.1396).
6,7-Methylenedioxy-4-(2-morpholin-4-yl-ethyl)-9-(3,4,5-trimethoxyphenyl)--
4,9-dihydro-3H-furo[3,4-b]quinolin-1-one (22). Purification: sgc
chromatography (9:1 EtOAc-CH.sub.3OH) as colorless crystals, 0.14 g
(68%). Recrystallized by slow evaporation from
CH.sub.2Cl.sub.2--CH.sub.3OH: mp 186-189.degree. C.; NMR
(CDCl.sub.3, 300 MHz) .delta. 6.47 (1H, s), 6.45 (1H, s), 6.27 (2H,
s), 5.83 (2H, s), 4.85 (1H, s), 4.80 (2H, bs), 3.67 (9H, s), 3.66
(4H, t, J=4.8 Hz), 3.61 (2H, m), 2.56 (2H, t, J=6 Hz) 2.40 (4H, m);
.sup.13C NMR (CDCl.sub.3, 125 MHz) .delta. 173.28, 158.22, 152.93,
147.52, 144.14, 141.63, 136.58, 130.98, 118.62, 110.75, 105.17,
101.54, 97.19, 94.96, 66.53, 65.43, 60.53, 55.92, 55.70, 53.94,
44.34, 40.49; (+)-HRAPCIMS m/z 511.2082 [M+4].sup.+ (calcd for
C.sub.27H.sub.30N.sub.2O.sub.8, 511.2080).
Benzo[1,3]dioxol-5-yl-(4-fluoro-benzyl)-1,2-diamine (23a).
Purification: sgc chromatography (3:1 CH.sub.2Cl.sub.2-hexanes),
light tan oil, 0.14 g (14%); .sup.1H NMR (CDCl.sub.3, 300 MHz)
.delta. 7.22 (2H, m), 6.93 (2H, m) 6.55 (1H, d, J=8.1 Hz), 6.15
(1H, d, J=2.1 Hz), 5.97 (1H, dd, J.sub.1=8.1 Hz, J.sub.2=2.1 Hz),
5.75 (2H, s), 4.13 (2H, s), 3.70 (1H, bs); .sup.13C NMR
(CDCl.sub.3, 125 MHz) maleate .delta. 172.34, 166.85, 164.87,
151.23, 150.17, 138.09, 135.05, 134.98, 132.60, 129.31, 118.73,
118.60, 118.43, 111.26, 106.49, 104.65, 57.63; (+)-HRFABMS m/z
246.0920 [M+H].sup.+ (calcd for C.sub.14H.sub.12NO.sub.2F,
246.0930).
6,7-Methylenedioxy-4-(4-fluoro-benzyl)-9-(3,4,5-trimethoxyphenyl)-4,9-dih-
ydro-3H-furo[3,4-b]quinolin-1-one (23). Purification: sgc
chromatography (2:1 hexanes-EtOAc.fwdarw.4:1 EtOAc-hexanes), light
yellow crystals, 0.10 g (46%). Recrystallized from EtOAc and from
EtOAc-hexanes: mp 246-247.degree. C.; .sup.1H NMR (CDCl.sub.3, 300
MHz) .delta. 7.23 (2H, m), 7.06 (2H, m), 6.58 (1H, s), 6.43 (2H,
s), 6.40 (1H, s), 5.90 (1H, d, J=1 Hz), 5.88 (1H, d, J=1 Hz), 5.06
(1H, s), 4.85 (1H, d, J=15 Hz), 4.77 (2H, s), 4.76 (1H, d, J=15
Hz), 3.81 (3H, s) 3.79 (6H, s); .sup.13C NMR (CDCl.sub.3, 125 MHz)
.delta. 172.41, 157.60, 153.21, 147.52, 144.37, 141.43, 136.80,
131.77, 130.66, 127.32, 127.25, 118.45, 116.46, 116.29, 110.75,
105.11, 101.61, 98.26, 95.81, 65.05, 60.74, 56.07, 49.08, 40.71;
(+)-HRAPCIMS m/z 506.1613 [M+H].sup.+ (calcd for
C.sub.28H.sub.24NO.sub.7F, 506.1615); anal. C, 66.19; H, 5.10; N,
2.81%, calcd for C.sub.28H.sub.24NO.sub.7F: C, 66.53; H, 4.79; N,
2.77%.
Benzo[1,3]dioxol-5-yl-(2-pyridin-2-ylethyl)-1,2-diamine (24a).
Purification: sgc chromatography (4:1 EtOAc-CH.sub.2Cl.sub.2),
brown oil, 0.155 g (14%); .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.
8.54 (1H, d, J=4.5 Hz), 7.58 (1H, dd, J.sub.1=7.8 Hz, J.sub.2=1.8
Hz), 7.15 (2H, m,), 6.65 (1H, d, J=8.7 Hz), 6.25 (1H, d, J=2.1 Hz),
6.07 (1H, dd, J.sub.1=8.7 Hz, J.sub.2=2.1 Hz), 5.82 (2H, s), 3.93
(1H, bs), 3.45 (2H, t, J=6.6 Hz), 3.05 (2H, t, J=6.6 Hz); .sup.13C
NMR (CDCl.sub.3, 125 MHz) maleate .delta. 169.18, 156.71, 148.67,
145.26, 145.13, 141.35, 135.22, 134.58, 125.78, 123.66, 112.00,
108.78, 101.62, 101.10, 48.98, 31.58; (+)-HRFABMS m/z
C.sub.14H.sub.14N.sub.2O.sub.2, 243.1115 [M+H].sup.+ (calcd for
C.sub.14H.sub.14N.sub.2O.sub.2, 243.1134).
6,7-Methylenedioxy-4-(2-pyridin-2-yl-ethyl)-9-(3,4,5-trimethoxyphenyl)-4,-
9-dihydro-3H-furo[3,4-b]quinolin-1-one (24). Purification: sgc
chromatography (30:1 EtOAc-CH.sub.3OH), light tan crystals, 0.10 g
(39%). Recrystallized from EtOAc-CH.sub.3OH: mp 239-241.degree. C.;
.sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 8.57 (1H, d, J=3.9 Hz),
7.56 (1H, dd, J.sub.1=7.5 Hz, J.sub.2=2.1 Hz), 7.17 (1H, m), 7.08
(1H, d, J=7.5 Hz), 6.77 (1H, s), 6.58 (1H, s), 6.37 (2H, s), 5.97
(1H, d, J=1.8 Hz), 5.96 (1H, d, J=1.2 Hz), 4.95 (1H, s), 4.62 (1H,
s), 4.61 (1H, s), 4.00 (2H, m), 3.79 (3H, s), 4.77 (6H, s), 3.19
(2H, m); .sup.13C NMR (CDCl.sub.3, 125 MHz,) .delta. 172.76,
157.93, 156.95, 152.95, 149.35, 147.52, 144.05, 141.56, 137.01,
136.65, 131.12, 123.77, 122.29, 118.71, 110.75, 105.21, 101.51,
97.06, 95.26, 65.22, 60.56, 56.01, 45.83, 40.53, 35.55; (+)-HRFABMS
m/z 503.1836 [M+H].sup.+ (calcd for C.sub.28H.sub.26N.sub.2O.sub.7,
503.1818).
Benzo[1,3]dioxol-5-yl-[2-(4-fluorophenyl)-ethyl]-1,2-diamine (25a).
Purification: sgc chromatography (2:1 CH.sub.2Cl.sub.2-hexanes),
light tan oil, 0.28 g (27%); .sup.1H NMR (CDCl.sub.3, 300 MHz)
.delta. 7.06 (2H, m), 6.92 (2H, m), 6.57 (1H, d, J=8.1 Hz), 6.15
(1H, d, J=2.1 Hz), 5.96 (1H, dd, J.sub.1=8.1 Hz, J.sub.2=2.1 Hz),
5.76 (2H, s), 3.33 (1H, bs), 3.23 (2H, t, J=6.9 Hz), 2.78 (2H, t,
J=6.9 Hz); .sup.13C NMR (CDCl.sub.3, 100 MHz) maleate
.delta.169.67, 148.76, 148.15, 135.47, 130.37, 130.28, 129.99,
116.28, 115.71, 115.50, 108.81, 103.98, 102.13, 53.99, 31.28;
(+)-HRFABMS m/z 260.1077 [M+H].sup.+ (calcd for
C.sub.15H.sub.14NO.sub.2F, 260.1087).
6,7-Methylenedioxy-4-[2-(4-fluorophenyl)-ethyl]-9-(3,4,5-trimethoxyphenyl-
)-4,9-dihydro-3H-furo[3,4-b]quinolin-1-one (25). Purification: sgc
chromatography (4:1 CH.sub.2Cl.sub.2-EtOAc) as light yellow
amorphous solid, 0.07 g (31%). Recrystallized from EtOAc: mp
174-177.degree. C.; .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.10
(2H, m), 6.96 (2H, m), 6.66 (1H, s), 6.59 (1H, s), 6.41 (2H, s),
5.98 (1H, s), 5.97 (1H, s), 4.99 (1H, s), 4.35 (1H, d, J=15.2 Hz),
4.30 (1H, d, J=15.2 Hz), 3.79 (9H, s), 3.65 (2H, m), 2.99 (2H, t,
J=7.2 Hz); .sup.13C NMR (CDCl.sub.3, 125 MHz) .delta. 172.55,
157.54, 153.16, 147.70, 144.24, 136.97, 133.08, 133.05, 131.18,
130.30, 130.23, 130.14, 118.70, 115.73, 115.64, 111.14, 105.55,
101.69, 97.28, 95.06, 64.98, 60.74, 56.24, 48.35, 40.59, 33.19;
(+)-HRFABMS m/z 520.1808 [M+H].sup.+ (calcd for
C.sub.29H.sub.26NO.sub.7F, 520.1772).
Benzo[1,3]dioxol-5-yl-[2-(4-chlorophenyl)-ethyl]-1,2-diamine (26a).
Purification: sgc chromatography (100% CH.sub.2Cl.sub.2), light tan
oil, 0.063 g (10%); .sup.1H NMR (CDCl.sub.3, 300 MHz,) .delta. 7.26
(2H, m), 7.13 (2H, m), 6.65 (1H, d, J=8.4 Hz), 6.23 (1H, d, J=2.1
Hz), 5.96 (1H, dd, J.sub.1=8.4 Hz, J.sub.2=2.1 Hz), 5.85 (2H, s),
3.44 (1H, bs), 3.31 (2H, t, J=6.6 Hz), 2.86 (2H, t, J=6.6 Hz);
.sup.13C NMR (CDCl.sub.3, 125 MHz) maleate .delta. 170.61, 151.44,
150.77, 138.22, 137.38, 135.67, 132.85, 132.78, 131.58, 118.87,
111.50, 106.61, 104.81, 56.37, 34.18; (+)-HRAPCIMS m/z 276.0795
[M+H].sup.+ (calcd for C.sub.15H.sub.14NO.sub.2.sup.35Cl,
276.0791).
6,7-Methylenedioxy-4-[2-(4-chlorophenyl)-ethyl]-9-(3,4,5-trimethoxyphenyl-
)-4,9-dihydro-3H-furo[3,4-b]quinolin-1-one (26). Purification: sgc
chromatography (15:1 CH.sub.2Cl.sub.2--CH.sub.3OH), pale yellow
amorphous solid, 0.03 g (30%). Recrystallized from
CH.sub.2Cl.sub.2-hexanes: mp 170-173.degree. C.; .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta. 7.26 (2H, m), 7.08 (2H, m), 6.65 (1H,
s), 6.60 (1H, s), 6.41 (2H, s), 5.98 (1H, s), 5.97 (1H, s), 4.99
(1H, s), 4.39 (1H, d, J=15.4 Hz), 4.33 (1H, d, J=15.4 Hz), 3.80
(9H, s), 3.66 (2H, m), 2.99 (2H, t, J=7.2 Hz); (+)-HRFABMS m/z
538.1442 [M+H].sup.+ (calcd for C.sub.29H.sub.26NO.sub.7.sup.37Cl,
538.1447).
Benzo[1,3]dioxol-5-yl-[2-(4-nitrophenyl)-ethyl]-1,2-diamine (27a).
Purification: bac chromatography (100% CH.sub.2Cl.sub.2), light tan
oil, 0.166 g (14%); .sup.1H NMR (CDCl.sub.3, 300 MHz,) .delta. 8.06
(2H, d, J=9 Hz), 7.26 (2H, d, J=9 Hz), 6.65 (1H, d, J=8.4 Hz), 6.13
(1H, d, J=2.4 Hz), 5.94 (1H, dd, J.sub.1=8.4 Hz, J.sub.2=2.4 Hz),
5.76 (2H, s), 3.29 (2H, t, J=6.9 Hz), 2.90 (2H, t, J=6.9 Hz);
(+)-HRAPCIMS m/z 287.1021 [M+H].sup.+ (calcd for
C.sub.15H.sub.14N.sub.2O.sub.4, 287.1032).
6,7-Methylenedioxy-4-[2-(4-nitrophenyl)-ethyl]-9-(3,4,5-trimethoxyphenyl)-
-4,9-dihydro-3H-furo[3,4-b]quinolin-1-one (27). Purification: bac
chromatography (1:1 CH.sub.2Cl.sub.2-EtOAc), light yellow amorphous
solid, 0.076 g (24%). Recrystallized from EtOAc: mp 188-190.degree.
C.; .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.94 (2H, d, J=9 Hz),
7.18 (2H, d, J=9 Hz), 6.50 (1H, s), 6.40 (1H, s), 6.20 (2H, s),
5.79 (1H, s), 5.78 (1H, s), 4.77 (1H, s), 4.34 (1H, d, J=15.5 Hz),
4.30 (1H, d, J=15.5 Hz), 3.68 (2H, m), 3.59 (6H, s), 3.58 (3H, s),
2.96 (2H, t, J=7.2 Hz); (+)-HRFABMS m/z 547.1703 [M+H].sup.+ (calcd
for C.sub.29H.sub.26N.sub.2O.sub.9, 547.1716).
Benzo[1,3]dioxol-5-yl-(3-imidazol-1-yl-propyl)-1,2-diamine (28a).
Purification: sgc chromatography (1:1 CH.sub.2Cl.sub.2-hexanes),
light tan oil, 0.12 g (12%); .sup.1H NMR (CDCl.sub.3, 300 MHz)
.delta. 7.36 (1H, s), 6.96 (1H, s), 6.81 (1H, s), 6.53 (1H, d,
J=8.1 Hz), 6.10 (1H, d, J=1.8 Hz), 5.94 (1H, dd, J, =8.1 Hz,
J.sub.2=1.8 Hz), 5.74 (2H, s), 3.96 (2H, t, J=6.9 Hz), 2.95 (2H, t,
J=6.9 Hz), 1.95 (2H, sept., J=7.2 Hz); (+)-HRAPCIMS m/z 246.1240
[M+H].sup.+ (calcd for C.sub.13H.sub.15N.sub.3O.sub.2,
246.1243).
6,7-Methylenedioxy-4-(3-imidazol-1-yl-propyl)-9-(3,4,5-trimethoxyphenyl)--
4,9-dihydro-3H-furo[3,4-b]quinolin-1-one (28). Purification: sgc
chromatography (3:1 EtOAc/CH.sub.3OH) as yellow glass, 0.043 g
(10%). Recrystallized from hot EtOAc: mp 206.degree. C. (dec);
.sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.56 (1H, bs), 7.15 (1H,
bs), 6.92 (1H, bs), 6.54 (1H, s), 6.35 (2H, s), 6.34 (1H, s), 5.94
(1H, s), 5.93 (1H, s), 4.93 (1H, s), 4.55 (2H, s), 4.04 (2H, t,
J=7.2 Hz), 3.76 (3H, s), 3.74 (6H, s), 3.46 (2H, m), 2.19 (2H, m);
(+)-HRAPCIMS m/z 506.1937 [M+H].sup.+ (calcd for
C.sub.27H.sub.27N.sub.3O.sub.7, 506.1927).
Benzo[1,3]dioxol-5-yl-(furan-2-ylmethyl)-1,2-diamine (32a).
Purification: sgc chromatography (7:1 hexanes-EtOAc.fwdarw.5:1
hexanes-EtOAc), tan oil, 0.22 g (24%); .sup.1H NMR (CDCl.sub.3, 300
MHz) .delta. 7.37 (1H, bs), 6.67 (1H, dd, J.sub.1=8.4 Hz,
J.sub.2=1.8 Hz), 6.34 (1H, d, J=0.9 Hz), 6.32 (1H, d, J=2.4 Hz),
6.23 (1H, d, J=0.9 Hz), 6.13 (1H, dd, J.sub.1=8.1 Hz, J.sub.2=2.18
Hz), 5.86 (1H, s), 5.85 (1H, s), 3.96, 4.26 (2H, s); (+)-HRAPCIMS
m/z 218.0817 [M+H].sup.+ (calcd for C.sub.12H.sub.11NO.sub.3,
218.0817).
6,7-Methylenedioxy-9-(4-hydroxy-3,5-dimethoxy-phenyl)-4,9-dihydro-3H-furo-
[3,4-b]quinolin-1-one (29). A stirred solution of ethanol (35 mL),
syringaldehyde (0.51 g, 0.0027 mol), and tetronic acid (270 mg,
0.0027 mol), and 3,4 methylenedioxy aniline (380 mg, 0.0027 mol)
were heated at reflux for 45 min. The product crystallized from the
solution upon cooling. After collection and recrystallization from
hot CH.sub.3OH-acetone (.about.1 L) was performed, the product was
again quickly recovered from cooling to provide a light tan powder
(87%, 0.90 g): mp 275.degree. C. (dec); .sup.1H NMR (DMSO-d.sub.6,
300 MHz) .delta. 9.67 (1H, s), 8.02 (1H, bs), 6.53 (1H, s), 6.40
(1H, s), 6.32 (2H, s), 5.83 (1H, s), 5.78 (1H, s), 4.85 (1H, d,
J=15.3 Hz), 4.70 (1H, d, J=15.3 Hz), 4.68 (1H, s), 3.57 (6H, s);
.sup.13C NMR (DMSO-d.sub.6, 100 MHz) .delta. 172.14, 158.21,
147.86, 146.32, 143.15, 137.41, 134.27, 130.23, 117.02, 109.55,
105.18, 101.10, 97.20, 94.36, 64.85, 56.03; (+)-HRFABMS m/z
384.0888 [M+H].sup.+ (calcd for C.sub.20H.sub.17NO.sub.7,
384.1083).
TBDMS Protected Syringaldehyde. To a stirred solution of
CH.sub.2Cl.sub.2 (75 mL), syringaldehyde (2.65 g, 0.0143 mol),
imidazole (4.43 g, 0.06 mol), and TBDMS-Cl (6.59 g, 0.044 mol) in
CH.sub.2Cl.sub.2 (20 mL) were added slowly, and the solution turned
cloudy over 16 h. The CH.sub.2Cl.sub.2 phase was washed with water,
dried, and the solvent was removed in vacuo to afford a light oil.
The oil was separated by sgc chromatography (2:1 EtOAc-hexanes)
yielding a colorless amorphous solid upon standing at rt (93%, 3.95
g): mp 70-72.degree. C.; .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.
9.74 (1H, s), 7.00 (2H, s), 3.77 (6H, s), 0.915 (9H, s), 0.062 (6H,
s), consistent with the literature..sup.27
6,7-Methylenedioxy-4-(cyclopentyl)-9-(4-hydroxy-3,5-dimethoxy-phenyl)-4,9-
-dihydro-3H-furo[3,4-b]quinolin-1-one (30) and 4'-TBDMS protected
30. This was prepared from a stirred solution of ethanol (15 mL),
and amine 18a (0.31 g, 0.0015 mol) was reacted with tetronic acid
(163 mg, 0.001 mol), and TBDMS-protected syringaldehyde (0.44 mg,
0.0015 mol). The product was isolated using sgc chromatography
(1:10 EtOAc-CH.sub.2Cl.sub.2) to yield TBDMS protected 30 as a
colorless amorphous powder 0.22 g (25%): .sup.1H NMR (CDCl.sub.3,
300 MHz) .delta. 6.63 (1H, s), 6.57 (1H, s), 6.33 (2H, s), 5.93
(1H, s), 5.92 (1H, s), 4.93 (1H, d, J=14.7 Hz), 4.85 (1H, s), 4.74
(1H, d, J=14.7 Hz), 4.16 (1H, sept., J=8.7 Hz), 3.69 (6H, s), 2.00
(6H, m), 1.74 (2H, m), 0.97 (9H, s), 0.08 (6H, s). Cleavage of the
silyl protecting group was achieved using a stirred solution of THF
(20 mL), 4'-TBDMS protected 30 (0.22 g, 0.00038 mol), and TBAF (0.5
mL added dropwise) with the solution stirred under Ar for 35 min.
TLC showed no starting material, and so the reaction mixture was
diluted with H.sub.2O (3.times.15 mL) and extracted with
CH.sub.2Cl.sub.2 (3.times.15 mL). The organic phase was dried and
the solvent was removed in vacuo. By means of sgc chromatography
(10:1 CH.sub.2Cl.sub.2-EtOAc.fwdarw.5:1 CH.sub.2Cl.sub.2-EtOAc)
separation, the product 30 was isolated as light yellow crystals,
0.127 g (74%). Recrystallized from CH.sub.2Cl.sub.2--CH.sub.3OH: mp
221-223.degree. C.; .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 6.55
(1H, s), 6.48 (1H, s), 6.29 (2H, s), 5.85 (1H, s), 5.83 (1H, s),
5.33 (1H, bs), 4.83 (1H, d, J=15.3 Hz), 4.77 (1H, s), 4.65 (1H, d,
J=15.3 Hz), 4.07 (1H, p, J=9 Hz), 3.70 (6H, s), 1.91 (6H, m), 1.67
(2H, m); .sup.13C NMR (CDCl.sub.3, 125 MHz) .delta. 172.65, 158.46,
146.94, 146.76, 143.91, 137.14, 133.50, 131.75, 120.16, 110.67,
104.24, 101.56, 99.86, 97.51, 65.88, 60.41, 56.22, 40.49, 28.59,
28.27, 24.84, 24.86; (+)-HRFABMS m/z 452.1698 [M+H].sup.+ (calcd
for C.sub.25H.sub.25NO.sub.7, 452.1709); anal. C, 63.87; H, 6.06;
N, 2.84%, calcd for C.sub.25H.sub.25NO.sub.7+H.sub.2O, C, 63.96; H,
5.80; N, 2.98%.
6,7-Methylenedioxy-4-[2-(4-fluorophenyl)-ethyl]-9-(4-hydroxy-3,5-dimethox-
y-phenyl)-4,9-dihydro-3H-furo[3,4-b]quinolin-1-one (31) and
4'-TBDMS Protected 31. The preceding reaction sequence was repeated
with ethanol (15 mL), amine 25a (0.220 g, 0.00085 mol), tetronic
acid (91 mg, 0.00085 mol), and TBDMS-protected syringaldehyde (0.31
mg, 0.00085 mol). In this case, the solution was heated at reflux
for 2 h. Upon cooling, the product crystallized from solution and
was recrystallized from hot CH.sub.3OH yielding colorless crystals
of 4'-TBDMS protected 31 (0.165 g, 30%). .sup.1H NMR (CDCl.sub.3,
300 MHz) .delta. 7.10 (2H, m), 6.96 (2H, m), 6.65 (1H, s), 6.60
(1H, s), 6.38 (2H, s), 5.97 (2H, s), 4.97 (1H, s), 4.37 (1H, d,
J=14.7 Hz), 4.23 (1H, d, J=14.7 Hz), 3.73 (6H, s,), 3.60 (2H, m,),
2.99 (2H, t, J=6.6 Hz), 0.99 (9H, s), 0.01 (6H, s). Cleavage of the
silyl protecting group was again conducted with anhydrous THF (15
mL), TBDMS-protected 31 (0.16 g, 0.00027 mol), and TBAF (0.5 mL).
After stirring under Ar for 0.5 h, TLC showed no starting material.
The product was isolated as per 30 (above) followed by sgc
chromatography (30:1 CH.sub.2Cl.sub.2-EtOAc.fwdarw.10:1
CH.sub.2Cl.sub.2-EtOAc.fwdarw.3:2 CH.sub.2Cl.sub.2-EtOAc) and
obtained as an off white powder 0.101 g (75%). Recrystallized from
hot CH.sub.3OH: mp 198-199.degree. C. (dec); .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta. 7.12 (2H, m), 6.96 (2H, m), 6.67 (1H,
s), 6.60 (1H, s), 6.44 (2H, s), 5.98 (1H, s), 5.97 (1H, s), 4.99
(1H, s), 4.37 (1H, d, J=15 Hz), 4.29 (1H, d, J=15 Hz), 3.83 (6H,
s), 3.70 (2H, m), 3.00 (2H, t, J=6.6 Hz); .sup.13C NMR (CDCl.sub.3,
100 MHz) .delta. 173.78, 158.42, 147.32, 147.17, 143.97, 136.73,
133.63, 133.13, 130.44, 130.09, 130.00118.70, 115.31, 115.10,
110.39, 105.01, 101.27, 96.05, 94.96, 65.06, 55.67, 39.85, 32.52,
29.93; (+)-HRAPCIMS m/z 506.1613 [M+H].sup.+ (calcd for
C.sub.28H.sub.24NO.sub.7F, 506.1615).
6,7-Methylenedioxy-4-(furan-2-ylmethyl)-9-(4-hydroxy-3,5-dimethoxy-phenyl-
)-4,9-dihydro-3H-furo[3,4-b]quinolin-1-one (32) and
4'-TBDMS-Protected 32: The preceding reaction sequence was repeated
with ethanol (15 mL), 32a (0.17 g, 0.00078 mol), tetronic acid (100
mg, 0.00078 mol), and TBDMS-protected syringaldehyde (0.28 mg,
0.00078 mol). The solution was heated at reflux for 1.5 h, and the
solvent was removed in vacuo to afford a yellow solid. The solid
was separated by sgc chromatography (30:1
CH.sub.2Cl.sub.2-EtOAc.fwdarw.400:15 CH.sub.2Cl.sub.2-EtOAc) and
the resulting yellow powder recrystallized from hot hexanes-EtOAc
yielding 4'-TBDMS protected 32 as an off-white powder (0.19 g,
43%): .sup.1H NMR (CDCl.sub.3, 300 MHz,) .delta. 7.37 (1H, d, J=1.5
Hz), 6.67 (1H, s), 6.54 (1H, s), 6.25 (1H, s), 6.24 (2H, s), 6.23
(1H, s), 5.84 (1H, s), 5.83 (1H, s), 4.97 (1H, s), 4.95 (1H, s),
4.92 (1H, s), 4.76 (1H, d, J=15.1 Hz), 4.63 (1H, d, J=15.1 Hz),
3.68 (6H, s), 0.89 (9H, s), 0.01 (6H, s); .sup.13C NMR (CDCl.sub.3,
100 MHz) .delta. 174.64, 159.23, 151.90, 149.08, 147.89, 144.90,
143.44, 139.43, 133.35, 131.69, 119.75, 111.11, 110.94, 109.49,
105.50, 102.10, 98.46, 96.18, 66.25, 55.94, 43.46, 41.04, 26.01,
19.00, 0.00; (+)-HRAPCIMS m/z 578.2212 [M+H].sup.+ (calcd for
C.sub.31H.sub.35NO.sub.8Si, 578.2210); anal. C, 64.30; H, 6.48; N,
2.55%, calcd for C.sub.31H.sub.35NO.sub.8Si, C, 64.45; H, 6.11; N,
2.42%. Cleavage of the silyl protecting group was again conducted
with anhydrous THF (15 mL), TBDMS-protected 32 (0.19 g, 0.00033
mol), and TBAF (1.0 mL). After 0.5 h under Ar, TLC showed no
starting material. The product was isolated as per 31 followed by
sgc chromatography (2:1 CH.sub.2Cl.sub.2-EtOAc) and was recovered
as a colorless powder, 0.132 g (85%). Recrystallized from hot
CH.sub.3OH-hexanes: mp 223-225.degree. C.; .sup.1H NMR (CDCl.sub.3,
300 MHz) .delta. 7.37 (1H, d, J=1.5 Hz), 6.68 (1H, s), 6.53 (1H,
s), 6.28 (2H, s), 6.35 (1H, s), 6.34 (1H, s), 5.91 (1H, d, J=1.8
Hz), 5.90 (1H, d, J=1.8 Hz), 4.97 (1H, s), 4.96 (1H, s), 4.94 (1H,
s), 4.74 (1H, d, J=15.3 Hz), 4.68 (1H, d, J=15.3 Hz), 3.78 (6H, s);
.sup.13C NMR (CDCl.sub.3, 100 MHz) .delta. 173.78, 158.37, 148.20,
147.13, 146.94, 143.97, 142.47, 136.78, 133.37, 130.66, 118.85,
109.91, 109.88, 108.53, 104.38, 101.14, 97.41, 95.26, 65.33, 55.39,
42.45, 40.01; (+)-HRAPCIMS m/z 464.1351 [M+H].sup.+ (calcd for
C.sub.25H.sub.2INO.sub.8, 464.1345); anal. C, 64.51; H, 4.97; N,
3.04%, calcd for C.sub.25H.sub.211\108, C, 64.79; H, 4.57; N,
3.06%.
General Procedure for the Synthesis of 4-Aza-podophyllotoxin
Structural Modifications: B and E ring Substitutions 15,.sup.25
15a-d, 15e-f.sup.2. The general synthetic procedure now follows for
compounds 15 and 15a-15f: A stirred solution of ethanol,
substituted aniline (I or II, 1 equiv.), tetronic acid (1 equiv.),
and benzaldehyde (III-VII, 1 equiv.) was heated at reflux and
monitored by TLC. The formation of the product was usually evident
(after 10 to 60 min) by the appearance of a bright blue spot when
viewed under UV. The solvent was then removed in vacuo and the
product was either recrystallized from, or purified using sgc
chromatography, with appropriate solvent systems.
6,7,8-Trimethoxy-9-(3,4,5-trimethoxyphenyl)-4,9-dihydro-3H-furo[3,4-b]qui-
nolin-1-one (15). Purification: recrystallized from CH.sub.3OH as
colorless amorphous crystals, 0.535 g (45%); mp 137-139.degree. C.;
1H NMR (CDCl.sub.3, 300 MHz) .delta. 8.29 (1H, s), 6.47 (2H, s),
6.29 (1H, s), 5.16 (1H, s), 4.69 (1H, d, J=16 Hz), 4.61 (1H, d,
J=16 Hz), 3.82 (3H, s), 3.78 (3H, s), 3.76 (3H, s), 3.74 (6H, s),
3.48 (3H, s); (+)-HRFABMS m/z 444.1659 [M+H].sup.+ (calcd for
C.sub.23H.sub.25NO.sub.8, 444.1658).
6,7,8-Trimethoxy-9-(3-bromo-4,5-trimethoxyphenyl)-4,9-dihydro-3H-furo[3,4-
-b]quinolin-1-one (15a). Purification: sgc chromatography (4:2:1
hexanes-EtOAc-CH.sub.3OH) obtained as colorless crystals, 0.584 g
(50%). Recrystallized from acetone-CH.sub.3OH: mp 175-177.degree.
C.; .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 8.41 (1H, s), 6.93
(1H, s), 6.81 (1H, s), 5.16 (1H, s), 4.75 (1H, d, J=15.8 Hz), 4.66
(1H, d, J=15.8 Hz), 3.88 (3H, s), 3.85 (3H, s), 3.81 (3H, s), 3.80
(3H, s), 3.53 (3H, s); .sup.13C NMR (CDCl.sub.3, 125 MHz) .delta.
173.90, 157.69, 153.59, 152.38, 144.69, 143.66, 138.65, 132.66,
123.72, 117.29, 111.96, 109.83, 97.26, 95.70, 65.67, 60.88, 60.59,
60.40, 56.16, 56.05, 35.48; (+)-HRAPCIMS m/z 494.0628 [M+H].sup.+
(calcd for C.sub.22H.sub.22NO.sub.7.sup.81Br, 494.0637); anal. C,
53.22; H, 4.74; N, 2.86%, calcd for
C.sub.22H.sub.22NO.sub.7.sup.81Br, C, 53.67; H, 4.50; N, 2.85%.
3-(TBDMS-O)-4-methoxybenzaldehyde. A stirred solution of
CH.sub.2Cl.sub.2 (30 mL), TBDMSCl (1.38 g, 0.008 mol), and
imidazole (0.61 g, 0.008 mol) was stirred for 5 min. The solution
turned cloudy and 3-hydroxy-4-methoxybenzaldehyde was added slowly.
The reaction proceeded under Ar for 3 h and was terminated with
H.sub.2O (30 mL). The CH.sub.2Cl.sub.2 layer was dried, the solvent
was removed in vacuo, and sgc chromatography (4:1 hexanes-EtOAc)
was used to isolate the product,
3-(TBDMS-O)-4-methoxybenzaldehyde.sup.24,25 as a light yellow oil,
1.76 g, (83%); .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 9.68 (1H,
s); 7.31 (1H, dd, J.sub.1=8.4 Hz, J.sub.2=2.4 Hz), 7.25 (1H, d,
J=2.4 Hz), 6.80 (1H, d, J=8.4 Hz), 3.73 (3H, s), 0.89 (9H, s), 0.05
(6H, s).
6,7,8-Trimethoxy-9-(3-OTBDMS-4-methoxyphenyl)-4,9-dihydro-3H-furo[3,4-b]q-
uinolin-1-one (15b). A stirred solution of
3-(TBDMS-O)-4-methoxybenzaldehyde (1.99 g, 0.0075 mol) and ethanol
(30 mL) was heated to reflux. Next, 3,4,5-trimethoxyaniline (1.39
g, 0.0075 mol), and tetronic acid (0.76 g, 0.0075 mol) were added
and heating at reflux continued for 1.5 h. TLC showed that a bright
blue UV absorbing spot formed, and the product (15b) was isolated
with sgc chromatography (6:1 CH.sub.2Cl.sub.2/EtOAc) as a yellow
oil that solidified at room temperature to yield
6,7,8-trimethoxy-9-(3-OTBDMS-4-methoxyphenyl)-4,9-dihydro-3H-furo[3,4-b]q-
uinolin-1-one (15b) as an amorphous light yellow solid, 2.23 g
(58%). Recrystallized from EtOAc-hexanes: mp 169-171.degree. C.;
.sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.81 (1H, s), 6.63 (3H,
m), 6.16 (1H, s), 4.98 (1H, s), 4.54 (1H, s), 4.53 (1H, s), 3.73
(3H, s), 3.65 (3H, s), 3.60 (3H, s), 3.31 (3H, s), 0.82 (9H, s),
0.00 (6H, s); .sup.13C NMR (DMSO-d.sub.6, 125 MHz) .delta.176.71,
162.10, 157.55, 156.44, 153.53, 148.43, 144.48, 142.40, 137.89,
125.24, 124.78, 116.87, 115.06, 100.91, 100.32, 69.59, 65.08,
64.70, 60.57, 60.25, 39.17, 30.34, 22.88, 0.07; (+)-HRAPCIMS m/z
514.2280 [M+H].sup.+ (calcd for C.sub.27H.sub.36NO.sub.7Si,
514.2261); anal. C, 62.99; H, 6.79; N, 2.99%, calcd for
C.sub.27H.sub.36NO.sub.7Si, C, 63.13; H, 6.87; N, 2.73%.
6,7,8-Trimethoxy-9-(3-hydroxy-4-methoxyphenyl)-4,9-dihydro-3H-furo[3,4-b]-
quinolin-1-one (15c). TBAF (1 M solution in THF, 3.3 mL) was added
slowly to a stirred solution of silyl ether 15b (1.55 g, 0.0030
mol) in THF (50 mL), and the reaction was allowed to proceed for 1
h, at which point TLC showed no starting material present. The
reaction was terminated with H.sub.2O (30 mL) and the aqueous
portion was extracted with CH.sub.2Cl.sub.2 (3.times.30 mL). The
combined organic extractions were partitioned with 2 N KOH
(3.times.30 mL). The base extracts were combined, brought to pH 7
with 1 N HCl, and this solution was extracted with EtOAc
(3.times.35 mL). The organic extracts were combined, dried, and the
solvent removed in vacuo leaving a yellowish white solid that was
recrystalized from hot EtOAc to yield colorless crystals 0.95 g
(79%). Recrystallized from EtOAc: mp 297-299.degree. C.; .sup.1H
NMR (CDCl.sub.3, 300 MHz) .delta. 8.54 (1H, s), 6.68 (1H, d, J=8.4
Hz), 6.64 (2H, s), 6.55 (1H, d, J=8.1 Hz), 6.19 (1H, s), 5.69 (1H,
bs), 4.97 (1H, s), 4.45 (2H, s), 3.71 (3H, s), 3.65 (3H, s), 3.61
(3H, s), 3.34 (3H, s); .sup.13C NMR (DMSO-d.sub.6, 125 MHz) .delta.
172.46, 157.91, 153.09, 152.18, 146.46, 146.35, 140.37, 137.99,
133.60, 118.54, 115.55, 112.27, 110.94, 96.64, 96.02, 65.28, 60.80,
60.45, 56.17, 56.09, 35.05; (+)-HRAPCIMS m/z 400.1424 [M+H].sup.+
(calcd for C.sub.21H.sub.22NO.sub.7, 400.1396).
6,7-Methylenedioxy-9-(2,3-methylenedioxyphenyl)-4,9-dihydro-3H-furo[3,4-b-
]quinolin-1-one (15d). Purification: recrystallized from
acetone-CH.sub.3OH as a light brown powder, 0.55 g (62%); mp
324-327.degree. C.; .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta.
9.75 (1H, s), 6.30 (1H, d, J=1.2 Hz), 6.50 (1H, d, J=4.5 Hz), 6.46
(1H, s), 6.38 (1H, s, 1H), 5.90 (2H, d, J=18.6 Hz), 5.80 (2H, d,
J=18 Hz), 4.95 (1H, s), 4.83 (1H, d, J=15.9 Hz), 4.73 (1H, d,
J=15.9 Hz); .sup.13C NMR (DMSO-d.sub.6, 125 MHz) .delta. 181.39,
168.52, 156.39, 156.12, 153.42, 152.87, 139.85, 137.47, 125.46,
118.47, 118.39, 116.12, 110.71, 110.15, 106.91, 106.82, 101.92,
74.47, 43.24; (+)-HRFABMS m/z 352.0843 [M+H].sup.+ (calcd for
C.sub.19H.sub.14NO.sub.6, 352.0821); anal. C, 65.05; H, 4.08;
3.99%, calcd for C.sub.19H.sub.14NO.sub.6, C, 64.96; H, 3.73; N,
3.99%.
6,7-Methylenedioxy-9-(3,4,5-trimethoxyphenyl)-4,9-dihydro-3H-furo[3,4-b]q-
uinolin-1-one (15e)..sup.25 Purification: recrystallized from
acetone-CH.sub.3OH as a colorless powder, 8.32 g (72%). mp
273-275.degree. C.; .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta.
9.82 (1H, s), 6.65 (1H, s), 6.51 (1H, s), 6.47 (2H, s), 5.84 (1H,
s), 5.79 (1H, s), 4.85 (1H, d, J=15.9 Hz), 4.75 (1H, s), 4.74 (1H,
d, J=15.9 Hz), 3.59 (6H, s), 3.49 (3H, s), consistent with
literature data..sup.24,25
6,7-Dimethoxy-9-(3,4,5-trimethoxyphenyl)-3H-furo[3,4-b]quinolin-1-one
(15f).sup.25 A stirred mixture of toluene, olefin 15e (2.0 g) and
10% Pd/C (1.0 g) was heated at reflux as air was bubbled through
the solution. After oxidation for 72 h, the catalyst was collected
and the solvent was removed in vacuo leaving a white solid, which
recrystallized from EtOAc-CH.sub.3OH as a colorless amorphous
solid, 1.76 g (88%); mp dec 150.degree. C.; .sup.1H NMR
(DMSO-d.sub.6, 400 MHz) .delta. 7.50 (1H, s), 7.04 (1H, s), 6.70
(2H, s), 6.26 (2H, s), 5.39 (2H, s), 3.76 (3H, s), 3.74 (6H, s).
.sup.13C NMR (DMSO-d6, 100 MHz) .delta. 168.35, 163.38, 153.59,
153.14, 150.50, 149.14, 148.25, 138.28, 128.13, 123.91, 112.47,
107.69, 105.43, 103.59, 102.22, 69.42, 60.62, 56.56; (+)-HRAPCIMS
m/z 396.1016 [M+H].sup.+ (calcd for C.sub.21H.sub.17NO.sub.7,
396.1083).
6,7-Methylenedioxy-4-methyl-9-(3,4,5-trimethoxyphenyl)-4,9-dihydro-3H-fur-
o[3,4-b]quinolin-1-one (16). To a stirred solution of anhydrous THF
(10 mL) and secondary amine 15e (0.30 g, 0.0008 mol) was added BuLi
(0.4 mL, 0.0008 mol, 2 M in THF). The solution turned deep red in
color and iodomethane (0.05 mL, 0.0008 mol) was added dropwise.
After 1.5 h under Ar, the reaction was terminated by slowly adding
H.sub.2O (20 mL). The aqueous phase was partitioned with
CH.sub.2Cl.sub.2 (3.times.30 mL). The combined organic extract was
dried and the solvent removed in vacuo. The N-methyl derivative 16
was obtained by sgc (4:1 CH.sub.2Cl.sub.2/EtOAc) and recrystallized
from hot EtOAc as a light yellow solid, 0.162 g (53%): mp
224-226.degree. C., [lit..sup.24 mp 226.degree. C.]; .sup.1HNMR
(CDCl.sub.3, 300 MHz) .delta. 6.58 (1H, s), 6.57 (1H, s), 6.40 (2H,
s), 5.95 (2H, d, J=1.5 Hz), 5.00 (1H, s), 4.86 (1H, d, J=15.9 Hz),
4.81 (1H, d, J=15.9 Hz), 3.79 (3H, s), 3.78 (6H, s); .sup.13C NMR
(CDCl.sub.3, 125 MHz) .delta. 172.65, 158.01, 153.16, 147.52,
144.16, 141.51, 136.82, 133.08, 118.26, 110.68, 105.23, 101.62,
97.42, 94.96, 65.00, 60.73, 56.17, 56.08, 40.67, 33.61;
(+)-HRAPCIMS m/z 412.1399 [M+H].sup.+ (calcd for
C.sub.22H.sub.21NO.sub.7, 412.1396), consistent with literature
data..sup.24
Cancer Cell Line Procedures. The human cancer cell growth
inhibition data were determined using the standard sulforhodamine B
assay of the US National Cancer Institute as previously
described..sup.35 In short, cells in a 5% fetal bovine
serum/RPMI1640 medium were inoculated in 96-well plates and
incubated for 24 h. Next, serial dilutions of the samples were
added. After 48 h, the plates were fixed with trichloroacetic acid,
stained with sulforhodamine B, and read with an automated
microplate reader. A growth inhibition of 50% (GI.sub.50 or the
drug concentration causing a 50% reduction in the net protein
increase) was determined from optical density data employing
Immunosoft.RTM. software. Table 2 shows the Murine P388 Lymphocytic
Leukemia Inhibitory Activity (ED50 .mu.g/mL) and Growth Inhibition
of Human Cancer Cell Lines (GI50 .mu.g/mL) for compounds of the
disclosure.
TABLE-US-00003 TABLE 2 cell line.sup.a compound P388 BXPC-3 MCF-7
SF-268 NCI-H460 KM20L2 DU-145 13 2.0 0.60 0.37 0.41 0.58 0.52 1.3
14 0.28 0.48 0.34 0.36 0.33 0.38 0.49 15 1.3 5.6 1.7 3.6 3.6
ND.sup.b 3.3 15a 0.11 0.56 0.12 0.11 0.35 ND.sup.b 0.42 15c 0.78
6.5 7.0 7.3 10.1 ND.sup.b >10 15d 0.17 0.065 0.0039 0.0089 0.021
ND.sup.b 0.041 15e.sup.c 0.0018 ND.sup.b ND.sup.b ND.sup.b ND.sup.b
ND.sup.b ND.sup.b 15f 3.6 4.1 3.4 2.4 2.8 2.1 2.4 16 0.027 0.049
0.034 0.029 0.032 0.032 0.026 17 0.24 0.040 0.026 0.026 0.028 0.032
0.047 18 15.3 0.083 0.045 0.062 0.16 0.12 0.27 19 3.4 0.17 0.052
0.066 0.27 0.24 0.27 20 0.18 0.43 0.29 0.46 1.0 0.51 2.5 21 1.7 4.4
>10 >10 >10 >10 >10 22 2.6 3.5 0.89 2.6 3.0 2.5 2.0
23 1.9 0.046 0.037 0.030 0.031 0.033 0.047 24 2.5 0.38 0.32 0.33
0.34 0.29 0.42 25 3.3 0.90 0.42 0.52 2.3 2.4 2.5 26 2.6 0.54 0.34
0.35 0.30 0.37 0.31 27 34.8 0.39 0.080 0.20 0.30 0.26 0.30 28 2.0
2.9 0.64 2.5 3.0 2.2 2.1 29 0.028 0.028 0.025 0.026 0.027 0.032
0.033 30 30.3 0.53 0.32 0.39 0.33 2.1 0.41 31 0.21 1.4 0.34 0.48
0.36 ND.sup.b 0.38 32 0.89 1.0 0.054 0.061 0.24 ND.sup.b 0.39
.sup.aCancer cell lines in order: murine lymphocytic leukemia
(P388); pancreas (BXPC-3); breast (MCF-7); CNS (SF-268); lung
(NCI-H460); colon (KM20L2) and prostate (DU-145). .sup.bND = not
determined see Ref. .sup.35. .sup.cSee Ref .sup.25.
From the results recorded in Table 2, some structure/activity
trends are evident. Podophyllotoxin derivatives with alkyl groups
in the 4-position revealed the most potent cancer cell growth
inhibitory activity (see substances 16.sup.24 and 17-19) and were
found selective for several cell lines, especially breast and CNS.
Short linkages between the aza-podophyllotoxin core and aromatic
substituents seem to be ideal, as evident in the order of magnitude
increase in cytostatic activity of 23 over 25. Several
4'-demethylated compounds were also synthesized. Although activity
remained good overall, it decreased with the removal of the
4'-methyl group in 18 vs. 30 in contrast compounds 25 vs. 31 have
nearly identical activities in most of the tested cell lines with
compound 31 appearing slightly more potent in a few cases.
REFERENCES
The following references are hereby incorporated by reference in
their entireties:
REFERENCES
(1) For Antineoplastic Agents. 584, see Pettit, G. R.; Ye, Q.;
Knight, J. C.; Hogan, F.; Melody, N.; Mukku, V. J. R. V.; Doubek,
D. L.; Chapuis, J.-C., in preparation. (2) Iwu, M. M.; Court, W. E.
Planta Med. 1980, 38, 260-263. (3) Addae-Mensah, I.; Achenbach, H.
Phytochemistry 1985, 24, 1817-1819. (4) Cimanga, K.; Ying, L.; De
Bruyne, T.; Apers, S.; Cos, P.; Hermans, N.; Bakana, P.; Tona, L.;
Kambu, K.; Kalenda, D. T.; Pieters, L.; Vanden Berghe, D.;
Vlietinck, A. J. J. Pharm. Pharmacol. 2001, 53, 757-761. (5)
Addae-Mensah, I.; Munenge, R. W. Fitoterapia 1989, 60, 359-362. (6)
Rashid, M. A.; Gustafson, K. R.; Cardellina, J. H., II; Boyd, M. R.
Nat. Prod. Lett. 2000, 14, 285-292. (7) Chang, L. C.; Song, L. L.;
Park, E. J.; Luyengi, L.; Lee, K. J.; Farnsworth, N. R.; Pezzuto,
J. M.; Kinghorn, A. D. J. Nat. Prod. 2000, 63, 1235-1238. (8)
Ikeda, R.; Nagao, T.; Okabe, H.; Nakano, Y.; Matsunaga, H.; Katano,
M.; Mori, M. Chem. Pharm. Bull. 1998, 46, 871-874. (9) Broomhead,
A. J.; Dewick, P. M. Phytochemistry 1990, 29, 3831-3837. (10)
Dossena, A.; Marchelli, R.; Pochini, A. J. Chem. Soc., Chem.
Commun. 1974, 771-772. (11) Marchelli, R.; Dossena, A.; Pochini,
A.; Dradi, E. J. Chem. Soc., Perkin Trans. 1 1977, 713-717. (12)
Pettit, G. R. J. Nat. Prod. 1995, 58, 359-364. (13) Hartwell, J.
L.; Schrecker, A. W. In Fortschritte der Chemie organischer
Naturstoffe, Vol. XV; Zechmeister, L., Ed.; Springer-Verlag:
Vienna, 1958; p 83. (14) Hearon, W. M.; MacGregor, W. S. Chem. Rev.
1955, 55, 957-1068. (15) (a) Mider, G. B. J. Nat. Cancer Inst.
1957, 19, 191-223. (b) Seliger, H. Der Krebsarzt 1955, 10, 357-360.
(16) Eyberger, A. L.; Dondapati, R.; Porter, J. R. J. Nat. Prod.
2006, 69, 1121-1124. (17) Wolff, S. N.; Hainsworth, J. D.; Greco,
F. A. J. Clin. Oncol. 2008, 26, 5310-5312. (18) Zhang, Y.-J.;
Litaudon, M.; Bousserouel, H.; Martin, M.-T.; Thoison, O.; Leonce,
S.; Dumontet, V.; Sevenet, T.; Gueritte, F. J. Nat. Prod. 2007, 70,
1368-1370. (19) (a) Wu, Y.; Zhao, J.; Chen, J.; Pan, C.; Li, L.;
Zhang, H. Org. Lett. 2009, 11, 597-600. (b) Wu, Y.; Zhang, H.;
Zhao, Y.; Zhao, J.; Chen, J.; Li, L. Org. Lett. 2007, 9, 1199-1202.
(20) (a) Zhang, Z.-J.; Tian, J.; Wang, L.-T.; Wang, M.-J.; Nan, X.;
Yang, L.; Liu, Y-Q.; Morris-Natschke, S. L.; Lee, K.-H.; Biorg.
Med. Chem. 2014, 22, 204-210. (b) Li, W.-Q.; Wang, X.-L.; Qian, K.;
Liu, Y.-Q.; Wang, C.-Y.; Yang, L.; Tian. J.; Morris-Natschke, S.
L.; Zhou, X.-W.; Lee, K.-H. Biorg. Med. Chem. 2013, 21, 2363-2369.
(c) Kamal, A.; Mallareddy, A.; Suresh, P.; Nayak, L.; Shetti, R. V.
C. R. N. C.; Rao, N. S.; Tamboli, J. R.; Shaik, T. B.;
Vishnuvardhan, M. V. P. S.; Ramakrishna, S. Eur. J. Med. Chem.
2012, 47, 530-545. (d) Wang, C.; Wu, Z.; Zhao, Y.; Ni, C.; Zhao,
X.; Zhu, L. Arch. Pharm. Chem. Life Sci. 2011, 344, 735-740. (e)
Jin, Y.; Liu, J.; Huang, W.-T.; Chen, S. W.; Hui, L. Eur. J Med.
Chem. 2011, 46, 4056-4061. (f) Singh, P.; Faridi, U.; Srivastava,
S.; Kumar, J. K.; Darokar, M. P.; Luqman, S; Shanker, K.;
Chanotiya, C. S.; Gupta, A.; Gupta, M. M.; Negi, A. N. Chem. Pharm.
Bull. 2010, 58, 242-246. (g) Castro, A. M.; del Corral, J. M. M.;
Garcia, P. A.; Rojo, M. V.; de la Iglesia-Vicente, J.; Mollinedo,
F.; Cuevas, C.; San Feliciano, A. J Med. Chem. 2010, 53, 983-993.
(h) Passarella, D.; Peretto, B.; Yepes, R. B.; Cappellettit, G.;
Cartelli, D.; Ronchi, C.; Snaith, J.; Fontana, G.; Danieli, B.;
Borlak, J. Eur. J. Med. Chem. 2010, 45, 219-226. (i) Yong, Y.;
Shin, S. Y.; Lee, Y. H.; Lim, Y. Bioorg. Med. Chem. Lett. 2009, 19,
4367-4371. (j) Zhi, X.; Yu, X.; Yang, C.; Ding, G.; Chen, H.; Xu,
H. Bioorg. Med. Chem. Lett., 2014, 24, 765-722. (k) Che, Z.; Yu,
X.; Zhi, X.; Fan, L.; Yao, X.; Xu, H. J. Agric. Food. Chem. 2013,
61, 8148-8155. (1) Xu, H.; He, X. Q.; Bioorg. Med. Chem. Lett.
2010, 20, 4503-4506. (m) Kamal, A.; Suresh, P.; Ramaiah, M. J.;
Mallarddy, A.; Kumar, B. A.; Raju, P.; Gopal, J. V.; Pushpavalli,
S. N. C. V. L.; Lavanya, A.; Sarma, P. Bioorg. Med. Chem. 2011, 19,
4589-4600. (n) Salerno, S.; Da Settuni, F.; Taliani, S.; Sunirubu,
F.; La Motta, C.; Fornaciari, G.; Marini, A. M. Curr. Med. Chem.
2010, 17, 4270-4290. (o) Zhang, Z. W.; Zhang, J. Q.; Hui, J.-Q.;
Chen, L. H.; Chen, S.-W.; Tian, X. Eur. J. Med. Chem. 2010, 45,
1673-1677. (p) Labruere, R.; Hautier, B.; Testud, M.; Seguin, J.;
Lenoir, C.; Desbene-Finck, S.; Helissey, P.; Garbay, C.; Chabot, G.
G.; Vidal, M.; Giorgi-Renault, S. ChemMedChem 2010, 5, 2016-2025.
(21) (a) Pettit, G. R.; Alkalay, D. S. J. Org. Chem. 1960, 25,
1363-1365. (b) Pettit, G. R.; Baumann, M. F.; Rangammal, K. N. J.
Med. Pharm. Chem. 1962, 5, 800-808. (22) Pinney, K. G.; Jelinek,
C.; Edvardsen, K.; Chaplin, D. J.; Pettit, G. R. In Anticancer
Agents from Natural Products; Cragg, G. M.; Kingston, D. G. I.;
Newman, D. J.; Eds.; Taylor and Francis: Boca Raton, Fla., 2005; pp
23-46. (23) (a) Wilstermann, A. M.; Bender, R. P.; Godfrey, M.;
Choi, S.; Anklin, C.; Berkowitz, D. B.; Osheroff, N.; Graves, D. E.
Biochemistry 2007, 46, 8217-8225. (b) Dong, W.; Zhang, L.; Niu, Y.;
Fan, D.; Wu, X.; Tang, X.; Cai, C. Expert Opin. Drug. Deliv. 2013,
10, 559-571. (24) (a) Tratrat, C.; Georgi-Renault, S.; Husson,
H.-P. Org. Lett. 2002, 4, 3187-3189. (b) Giorgi-Renault, S. Ann.
Pharm. Fr. 2005, 63, 63-68. (25) Hitotsuyanagi, Y.; Fukuyo, M.;
Tsuda, K.; Kobayashi, M.; Ozeki, A.; Itokawa, H.; Takeya, K.
Bioorg. Med. Chem. Lett. 2000, 10, 315-317. (26) Botes, M. G.;
Pelly, S. C.; Blackie, M. A. L.; Kornienko, A.; van Otterlo, W. A.
L. Chem. Heterocycl. Compd. 2014, 50, 119-137. (27) Wang, J. Z.;
Tian, X.; Tsumura, H.; Shimura, K.; Ito, H. Anticancer Drug Des.
1993, 8, 193-202. (28) Hanauske, A. R.; Wuester, K. C.; Lehmer, A.;
Rotter, M.; Schneider, P.; Kaeser-Froelich, A.; Rastetter, J.;
Depenbrock, H. Eur. J. Cancer, Part A 1995, 31A, 1677-1681. (29)
Utsugi, T.; Shibata, H.; Kumio, S.; Aoyagi, K.; Wierzba, K.;
Kobunai, T.; Terada, T.; Oh-hara, T.; Tsuruo, T.; Yamada, Y. Cancer
Res. 1996, 56, 2809-2814. (30) Lee, C. C.; Huang, T. S. Pharm. Res.
2001, 18, 846-851. (31) Kumar, A.; Alegria, A. E. J. Heterocycl.
Chem. 2010, 47, 1275-1282. (32) Snyder, H. R.; Konecky, M. S.;
Lennarz, W. J. J. Am. Chem. Soc. 1958, 80, 3611-3615. (33) Ley, S.
V.; Thomas, A. W. Angew. Chem. Intl. Ed. 2003, 42, 5400-5449. (34)
Beletskaya, I. P.; Cheprakov, A. V. Coord. Chem. Rev. 2004, 248,
2337-2364. (35) Monks, A.; Scudiero, D.; Skehan, P.; Shoemaker, R.;
Paull, K.; Vistica, D.; Hose, C.; Langley, J.; Cronise, P.;
Viagro-Wolff, A.; Gray-Goodrich, M.; Campbell, H.; Mayo, J.; Boyd,
M. J. Natl. Cancer Inst. 1991, 83, 757-766.
While particular materials, formulations, operational sequences,
process parameters, and end products have been set forth to
describe and exemplify this invention, they are not intended to be
limiting. Rather, it should be noted by those ordinarily skilled in
the art that the written disclosures are exemplary only and that
various other alternatives, adaptations, and modifications may be
made within the scope of the present invention. Accordingly, the
present invention is not limited to the specific embodiments
illustrated herein, but is limited only by the following
claims.
* * * * *